Oxazole derivatives

ABSTRACT

The present invention relates to compounds of formula (I) 
                         
wherein wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and n are as described herein. The compounds of the present invention can be used as medicaments for the treatment and/or prevention of diseases which are modulated by PPARα and/or PPARγ agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases (such as e.g. crown disease, inflammatory bowel disease, collitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as e.g. Alzheimer&#39;s disease or impaired/improvable cognitive function) and proliferative diseases.

PRIORITY TO RELATED APPLICATIONS

This application is a division of prior application Ser. No. 10/679,604,filed Oct. 6, 2003, now U.S. Pat. No. 6,969,725 which claims the benefitof European Application No. 02022286.5, filed Oct. 7, 2002; each ofwhich is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention is concerned with novel oxazole derivatives, theirmanufacture and their use as medicaments.

Peroxisome Proliferator Activated Receptors (PPAR's) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypesthereof have been identified and cloned. These include PPARα, PPARβ(also known as PPARδ), and PPARγ. There exist at least two majorisoforms of PPARγ. While PPARγ1 is ubiquitously expressed in mosttissues, the longer isoform PPARγ2 is almost exclusively found inadipocytes. In contrast, PPARα is predominantly expressed in the liver,kidney and heart. PPAR's modulate a variety of body responses includingglucose- and lipid-homeostasis, cell differentiation, inflammatoryresponses and cardiovascular events.

Diabetes is a disease in which a patient's ability to control glucoselevels in blood is impaired, because he has partially lost the abilityto respond properly to the action of insulin. In type II diabetes (T2D),often referred to as non-insulin dependent diabetes mellitus (NIDDM),which afflicts 80-90% of all diabetic patients in developed countries,the Isles of Langerhans in the pancreas still produce insulin. However,the target organs, mainly muscle, liver and adipose tissue, exhibit aprofound resistance to insulin stimulation, and the body compensates byproducing unphysiologically high levels of insulin. In later stage ofdisease, however, insulin secretion decreases due to exhaustion of thepancreas. In addition to that T2D is a metabolic-cardiovascular diseasesyndrome.

Among the comorbidities associated with T2D are for example insulinresistance, dyslipidemia, hypertension, endothelial dysfunction andinflammatory atherosclerosis. Current first line treatment for diabetesgenerally involves low fat—and glucose—diet and exercise. However,compliance can be moderate and as the disease progresses, treatment withhypoglycemic drugs, e.g. sulfonylureas or metformin, becomes necessary.A promising new class of drugs has recently been introduced thatresensitizes patients to their own insulin (insulin sensitizers),thereby reverting blood glucose and triglyceride levels to normal, andthus abolishing, or at least reducing, the requirement for exogenousinsulin. Pioglitazone (Actos™) and rosiglitazone (Avandia™) belong tothe thiazolidinediones (TZD) class of PPARγ-agonists and were the firstrepresentatives who had been approved for NIDDM in several countries.These compounds, however, suffer from side effects including rare butsevere liver toxicity (as seen with troglitazone), and they increasebody weight in humans. Therefore, new, better and more efficacious drugsfor the treatment of NIDDM are urgently needed. Recent studies provideevidence that a coagonism on PPARα and PPARγ would result in compoundswith enhanced therapeutic potential, i.e. such compounds should improvethe lipid profile in addition to the normalization of glucose- andinsulin-levels (Keller and Wahli: Trends Endocrin. Metab. 1993;4:291-296, Macdonald and Lane: Current Biology Vol. 5 pp. 618-621(1995)). Recent observations suggest furthermore that there is anindependent PPARα mediated effect on insulin-sensitization that couldresult secondary to the reduction in lipids (Guerre-Millo et al; J BiolChem 2000; 275: 16638-16642). Consequently, the incorporation of PPARαactivity into PPARγ agonists is expected to give rise to moreefficacious drugs for the treatment and/or prevention of diabetes.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula (I)

-   -   wherein R¹, R², R³, R⁴, R⁵, R⁶ and n are as described herein,    -   or pharmaceutically acceptable salts and/or pharmaceutically        acceptable esters thereof.

The novel compounds of the present invention exceed the compounds knownin the art, inasmuch as they bind to and activate both, PPARα and PPARγ,simultaneously and very efficiently. Therefore, these compounds combinethe anti-glycemic effect of PPARγ activation with the anti-dyslipidemiceffect of PPARα activation. Consequently, plasma glucose and insulin arereduced (=insulin sensitization), triglycerides lowered and HDLcholesterol increased (=improved lipid profile). In addition, suchcompounds may also lower LDL cholesterol, decrease blood pressure andcounteract inflammatory atherosclerosis. Since multiple facets of theT2D disease syndrome are addressed by PPARα and γ coagonists, they areexpected to have an enhanced therapeutic potential compared to thecompounds already known in the art.

The compounds of the present invention further exhibit improvedpharmacological properties compared to known compounds.

Unless otherwise indicated the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “halogen” refers to fluorine, chlorine, bromine and iodine.

The term “protecting group” refers to groups such as e.g. acyl,alkoxycarbonyl, aryloxycarbonyl, silyl, or imine-derivatives, which areused to temporarily block the reactivity of functional groups. Wellknown protecting groups are e.g. t-butyloxycarbonyl, benzyloxycarbonyl,fluorenylmethyloxycarbonyl or diphenylmethylene which can be used forthe protection of amino groups, or lower-alkyl-, β-trimethylsilylethyl-and β-trichloroethyl-esters, which can be used for the protection ofcarboxy groups.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms.

The term “lower-alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like.

The term “fluoro-lower-alkyl” refers to lower-alkyl groups which aremono- or multiply substituted with fluorine. Examples offluoro-lower-alkyl groups are e.g. CF₃, CF₃CH₂ and (CF₃)₂CH.

The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ islower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy.

The term “fluoro-lower-alkoxy” refers to the group R″—O—, wherein R″ isfluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are e.g.CF₃—O, CF₃CH₂—O and (CF₃)₂CH—O.

The term “lower-alkenyl”, alone or in combination signifies astraight-chain or branched hydrocarbon residue comprising an olefinicbond and up to 8, preferably up to 6, particularly preferred up to 4carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.A preferred example is 2-propenyl.

The term “lower-alkenyloxy” means a group R″—O—, wherein R″ islower-alkenyl. Examples of lower-alkenyloxy groups are butenyloxy,particularly but-3-enyloxy.

The term “fluoro-lower-alkenyloxy” refers to lower-alkenyloxy groups asdefined above, which are mono- or multiply substituted with fluorine.Examples of fluoro-lower-alkenyloxy groups are e.g. (Z) or (E)4,4,4-trifluoro-but-2-en-1-yl.

The term “aryl” relates to the phenyl or naphthyl group, preferably thephenyl group, which can optionally be mono- or multiply-substituted,particularly mono-, di- or tri-substituted by halogen, hydroxy, CN, CF₃,NO₂, NH₂, N(H, lower-alkyl), N(lower-alkyl)₂, carboxy, aminocarbonyl,lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, phenyl and/or phenyloxy.Preferred substituents are halogen, lower-alkyl, fluoro-lower-alkyland/or lower-alkoxy.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/orsulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl,isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term “heteroaryl”further refers to bicyclic aromatic groups comprising two 5- or6-membered rings, in which one or both rings can comprise 1, 2 or 3atoms selected from nitrogen, oxygen or sulphur such as e.g. indole orquinoline, or partially hydrogenated bicyclic aromatic groups such ase.g. indolinyl. A heteroaryl group may have a substitution pattern asdescribed earlier in connection with the term “aryl”. Preferredheteroaryl groups are e.g. thienyl and furyl which can optionally besubstituted as described above, preferably with halogen, CF₃,lower-alkyl and/or lower-alkoxy.

The term “pharmaceutically acceptable salts” embraces salts of thecompounds of formula (I) with pharmaceutically acceptable bases such asalkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- andMg-salts, and ammonium or substituted ammonium salts, such as e.g.trimethylammonium salts.

The compounds of formula (I) can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula (I) (hydration). The termpharmaceutically acceptable salts also includes pharmaceuticallyacceptable solvates.

The term “pharmaceutically acceptable esters” embraces derivatives ofthe compounds of formula (I), in which a carboxy group has beenconverted to an ester. Lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- ordi-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,pyrrolidino-lower-alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl,lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples ofsuitable esters. The methyl, ethyl, propyl, butyl and benzyl esters arepreferred esters. The methyl and ethyl esters are especially preferred.The term “pharmaceutically acceptable esters” furthermore embracescompounds of formula (I) in which hydroxy groups have been converted tothe corresponding esters with inorganic or organic acids such as, nitricacid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms.

DETAILED DESCRIPTION OF THE INVENTION

In detail, the present invention relates to compounds of formula (I)

wherein

-   -   R¹ is aryl or heteroaryl;    -   R² is hydrogen, lower-alkyl, or fluoro-lower-alkyl;    -   R³ and R⁴ independently from each other are hydrogen, hydroxy,        halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl,        lower-alkoxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy,        hydroxy-lower-alkoxy, lower-alkoxy-lower-alkoxy, or        lower-alkenyl,    -   wherein at least one of R³ and R⁴ is not hydrogen;    -   R⁵ is lower-alkoxy, fluoro-lower-alkoxy, lower-alkenyloxy,        fluoro-lower-alkenyloxy, aryloxy, aryl-lower-alkoxy, or        aryl-fluoro-lower-alkoxy;    -   R⁶ is hydrogen or lower-alkyl;    -   n is 1, 2 or 3;    -   or pharmaceutically acceptable salts and/or pharmaceutically        acceptable esters thereof.

Preferred are the compounds of formula (I)

-   -   wherein    -   R¹ is aryl or heteroaryl;    -   R² is hydrogen, lower-alkyl, or fluoro-lower-alkyl;    -   R³ and R⁴ independently from each other are hydrogen, hydroxy,        halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl,        lower-alkoxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy,        hydroxy-lower-alkoxy, lower-alkoxy-lower-alkoxy, or        lower-alkenyl,    -   wherein at least one of R³ and R⁴ is not hydrogen;    -   R⁵ is lower-alkoxy, fluoro-lower-alkoxy, lower-alkenyloxy,        fluoro-lower-alkenyloxy, aryloxy, aryl-lower-alkoxy, or        aryl-fluoro-lower-alkoxy;    -   R⁶ is hydrogen or lower-alkyl;    -   n is 1;        or pharmaceutically acceptable salts and/or pharmaceutically        acceptable esters thereof.

The compounds of formula (I) as described above comprise an asymmetriccarbon which is adjacent to R⁵. The carbon atom to which R⁵ is attachedis of the S configuration according to theCahn-Ingold-Prelog-Convention.

Compounds of formula (I) as defined above, wherein R¹ is aryl arepreferred.

Compounds, wherein R¹ is phenyl optionally substituted with 1 to 3substituents independently selected from the group consisting oflower-alkyl, lower-alkoxy, halogen, and fluoro-lower-alkyl are alsopreferred, with those compounds wherein R¹ is phenyl optionallysubstituted with 1 to 2 substituents independently selected from thegroup consisting of lower-alkyl, lower-alkoxy, and halogen being morepreferred, and with those compounds wherein R¹ is phenyl,2-methyl-phenyl, 4-isopropoxy-phenyl, 4-fluoro-3-methyl-phenyl,2-fluoro-phenyl, 4-isopropyl-phenyl, 2-ethoxy-4-fluoro-phenyl,3-methoxy-phenyl, or 4-tert-butyl-phenyl being particularly preferred.Compounds, in which R¹ is phenyl substituted with methyl and/or fluorineare preferred, particularly 2-methyl-phenyl or 2-fluoro-phenyl.

Furthermore, compounds as defined above in which R² is hydrogen orlower-alkyl are preferred, with hydrogen or methyl being particularlypreferred. Hydrogen and methyl individually constitute separatepreferred embodiments. Compounds in which R² is lower alkyl, preferablymethyl, are also preferred.

Compounds of formula (I), wherein R³ and R⁴ independently from eachother are hydrogen, hydroxy, halogen, lower-alkyl, fluoro-lower-alkyl,or lower-alkoxy, wherein at least one of R³ and R⁴ is not hydrogen alsorelate to a preferred embodiment of the present invention. Compounds,wherein R³ is hydrogen or methyl are preferred. Hydrogen and methylindividually relate to preferred embodiments of the present invention.Compounds as defined above, wherein R⁴ is methyl, ethyl, fluoro, chloro,trifluoromethyl, hydroxy, methoxy, ethoxy, or isopropoxy areparticularly preferred. Preferably, R³ is hydrogen and R⁴ islower-alkyl, particularly methyl.

Another preferred embodiment of the present invention relates tocompounds of formula (I) as defined above, wherein R⁵ is lower-alkoxy,more preferably methoxy or ethoxy, more preferably ethoxy. Otherpreferred compounds are those, wherein R⁶ is hydrogen.

Preferred compounds are those, wherein R¹ is phenyl substituted withmethyl and/or fluorine, R² is lower-alkyl, R³ is hydrogen, R⁴ islower-alkyl, R⁵ is lower-alkoxy, and R⁶ is hydrogen. More preferredcompounds are those, wherein R¹ is 2-methyl-phenyl or 2-fluoro-phenyl,R² is methyl, R³ is hydrogen, R⁴ is methyl, R⁵ is ethoxy, and R⁶ ishydrogen.

Compounds of formula (I), wherein n is 1, 2 or 3, individually relate topreferred embodiments of the present invention.

The pharmaceutically acceptable salts of the compound of formula (I) andthe pharmaceutically acceptable esters of the compounds of formula (I)individually constitute preferred embodiments of the present invention.Particularly preferred are compounds of formula (I).

Preferred compounds of general formula (I) are those selected from thegroup consisting of

-   (S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-3-{4-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-3-(4-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-3-[2-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-[2-Chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionic    acid,-   (S)-3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic    acid,-   (S)-2-Ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic    acid,-   (S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-[2,6-Dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic    acid,-   (S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic    acid,-   (S)-3-{4-[2-(3,5-Dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-{4-[2-(3,5-Dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic    acid,-   (S)-2-Ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-3-{4-[2-(2-Chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethoxy-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionic    acid,-   (S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionic    acid, and-   (S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Particularly preferred compounds of formula (I) are those selected fromthe group consisting of

-   (S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-3-[2-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionic    acid,-   (S)-3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic    acid,-   (S)-3-[2,6-Dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic    acid,-   (S)-2-Ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic    acid, and-   (S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionic    acid,-   and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Other particularly preferred compounds of formula (I) are those selectedfrom the group consisting of

-   (S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic    acid,-   (S)-3-[2-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-3-{2-Chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic    acid,-   (S)-3-[2,6-Dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic    acid,-   (S)-2-Ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic    acid,-   (S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic    acid, and-   (S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionic    acid,-   and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Each of the compounds mentioned above individually constitutes apreferred embodiment of the present invention, particularly(S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof. Another example of a preferred individualcompound is(S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid and pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof. Compounds as described above, which are notpharmaceutically acceptable salts and/or pharmaceutically acceptableesters are preferred.

Compounds of formula (I) have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, optically purediastereoisomers or mixtures of diastereoisomers. The optically activeforms can be obtained for example by resolution of the racemates, byasymmetric synthesis or asymmetric chromatography (chromatography with achiral adsorbens or eluant). The invention embraces all forms, whereinthe asymmetric carbon to which R⁵ is attached is of the S configuration.

It will be appreciated, that the compounds of general formula (I) inthis invention may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundin vivo. Physiologically acceptable and metabolically labilederivatives, which are capable of producing the parent compounds ofgeneral formula (I) in vivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula (I) as defined above, which processcomprises removing a protecting group in a compound of formula (II)

-   -   wherein R¹, R², R³, R⁴, R⁵ and n are as defined before and PG is        a protecting group.

Possible protecting groups PG in compounds of formula (II) are e.g.lower-alkyl-, β-trimethylsilylethyl- and β-trichloroethyl-esters, whichcan be used for the protection of the corresponding carboxy group.Lower-alkyl-ester protecting groups can be removed in the presence of abase such as e.g. LiOH or NaOH in a solvent such as e.g. H₂O, ethanol,tetrahydrofuran, or dioxan, or in a mixture of such solvents, e.g. in atemperature range of 10-50° C. The β-trichloroethyl-ester protectinggroup can be removed in the presence of Zn in acetic acid, e.g. in atemperature range of 10-50° C. The β-trimethylsilylethyl-esterprotecting group can be removed in the presence of tetrabutylammoniumfluoride in tetrahydrofuran, e.g. in a temperature range of 20-65° C.Methods for converting a compound of formula (I) as defined above to apharmaceutically acceptable salt are known in the art.

The invention further relates to compounds of formula (I) as definedabove, when manufactured according to a process as defined above.

As described above, the compounds of formula (I) of the presentinvention can be used as medicaments for the treatment and/or preventionof diseases which are modulated by PPARα and/or PPARγ agonists. Examplesof such diseases are diabetes, particularly non-insulin dependentdiabetes mellitus, elevated blood pressure, increased lipid andcholesterol levels, atherosclerotic diseases, metabolic syndrome,endothelial dysfunction, procoagulant state, dyslipidemia, polycysticovary syndrome, inflammatory diseases (such as e.g. crown disease,inflammatory bowel disease, collitis, pancreatitis, cholestasis/fibrosisof the liver, and diseases that have an inflammatory component such ase.g. Alzheimer's disease or impaired/improvable cognitive function) andproliferative diseases (cancers such as e.g. liposarcoma, colon cancer,prostate cancer, pancreatic cancer and breast cancer). The use asmedicament for the treatment and/or prevention of non-insulin dependentdiabetes mellitus is preferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutic active substances, particularly as therapeutic activesubstances for the treatment and/or prevention of diseases which aremodulated by PPARα and/or PPARγ agonists. Examples of such diseases arediabetes, particularly non-insulin dependent diabetes mellitus, elevatedblood pressure, increased lipid and cholesterol levels, atheroscleroticdiseases, metabolic syndrome, endothelial dysfunction, procoagulantstate, dyslipidemia, polycystic ovary syndrome, inflammatory diseasesand proliferative diseases, preferably non-insulin dependent diabetesmellitus.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are modulated byPPARαand/or PPARγ agonists, which method comprises administering acompound of formula (I) to a human or animal.

Preferred examples of such diseases are diabetes, particularlynon-insulin dependent diabetes mellitus, elevated blood pressure,increased lipid and cholesterol levels, atherosclerotic diseases,metabolic syndrome, endothelial dysfunction, procoagulant state,dyslipidemia, polycystic ovary syndrome, inflammatory diseases andproliferative diseases, preferably for the treatment and/or preventionof non-insulin dependent diabetes mellitus.

The invention further relates to the use of compounds as defined abovefor the treatment and/or prevention of diseases which are modulated byPPARαand/or PPARγ agonists. Preferred examples of such diseases arediabetes, particularly non-insulin dependent diabetes mellitus, elevatedblood pressure, increased lipid and cholesterol levels, atheroscleroticdiseases, metabolic syndrome, endothelial dysfunction, procoagulantstate, dyslipidemia, polycystic ovary syndrome, inflammatory diseasesand proliferative diseases, preferably non-insulin dependent diabetesmellitus.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprevention of diseases which are modulated by PPARα and/or PPARγagonists. Preferred examples of such diseases are diabetes, particularlynon-insulin dependent diabetes mellitus, elevated blood pressure,increased lipid and cholesterol levels, atherosclerotic diseases,metabolic syndrome, endothelial dysfunction, procoagulant state,dyslipidemia, polycystic ovary syndrome, inflammatory diseases andproliferative diseases, preferably non-insulin dependent diabetesmellitus. Such medicaments comprise a compound as defined above.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thetext or in the examples, or by methods known in the art.

Homochiral compounds of formula (I) (compounds 10 and 11 in scheme 1 andcompounds 6 and 7 in scheme 3) can be prepared according to the methodsdepicted in scheme 1 and 3 or by analogous methods.

Racemates of compounds of formula (I) [compounds 9 and compounds 10 inscheme 2 and compounds 9 and 11 in scheme 4] can e.g. be synthesizedaccording to the methods depicted in scheme 2 or 4 or by analogousmethods. The optically pure (S) enantiomer can then be prepared fromracemates of compounds of formula (I) by methods known in the art, suchas separation of the antipodes via diastereomeric salts bycrystallization with optically pure amines such as e.g. (R) or(S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine,brucine, quinine and quinidine or by separation of the antipodes byspecific chromatographic methods using either a chiral adsorbens or achiral eluent.

Homochiral alpha-alkoxy-phenyl-propionic acid esters of formula 10 andfree acids of formula 11 can be prepared according to the methoddepicted in scheme 1 or by analogous methods known in the art.

The well known chiral auxiliary 2 [(S)-4-benzyl-oxazolidin-2-one] iscondensed with an alkoxy-acetyl chloride 1 in the presence of a strongbase like n-butyl lithium in an inert solvent like tetrahydrofuran attemperatures around −78° C. to produce building block 3 (step a). Thelatter is then treated according to literature precedence [TetrahedronAsymmetry (1999), 10, 1353-1367] with dibutylboron-triflate and atertiary amine like triethylamine in dichloromethane to generate thecorresponding boron enolate, which is subsequently reacted at lowtemperatures with aldehydes 4 (prepared as outlined in scheme 5)resulting in compounds 5 (step b). In these aldol products 5, one of allfour possible stereoisomers is strongly predominating (stereochemistryas indicated without rigorous proof with respect to the benzylicposition). Compounds 5 are converted into phenolic intermediates 8 via athree step sequence encompassing: i) carefully controlled esterformation using only a minimal excess of alcoholate in the correspondingalcohol as solvent or in solvents like tetrahydrofuran or dioxane attemperatures ranging from −20° C. to room temperature to give estercompounds 6 (step c); ii) removal of the benzylic hydroxy group in 6with a reducing agent like e.g. triethylsilane in the presence of aLewis acid, like boron-trifluoride, or a protic acid, liketrifluoroacetic acid, in a suitable solvent like trifluoroacetic aciditself or dichloromethane between 0° C. and 60° C. to yield protectedphenol compounds 7 (step d); iii) ensuing removal of the protectinggroup, e.g. a benzyl group, by standard technology, e.g. catalytichydrogenation using hydrogen and a catalyst like palladium or by usingdimethyl sulfide and boron trifluoride diethyl etherate in a solventlike dichloromethane between room temperature and the reflux temperatureof the solvent to give phenolic compounds 8 (step e); the order of thethree reaction steps c, d, e is interchangeable, and catalytichydrogenation can also be used for the simultaneous removal of thebenzylic hydroxy function and a benzyl protecting group, preferablyusing palladium on charcoal as catalyst in the presence of an acid likeoxalic acid in solvents like alcohols at temperatures around roomtemperature and a hydrogen pressure up to 100 bar.

Aryl-oxazole compounds 9 (prepared as outlined in schemes 6 and 7) arecondensed with phenols 8 according to well known procedures: if R⁷represents a hydroxy group e.g. via Mitsunobu-reaction, withtriphenylphosphine and di-tert-butyl-, diisopropyl- ordiethyl-azodicarboxylate as reagents; this transformation is preferablycarried out in a solvent like toluene, dichloromethane ortetrahydrofuran at ambient temperature. Alternatively, if R⁷ representsa halide, mesylate or tosylate moiety, the aryl-oxazole compounds 9 canbe reacted with phenols 8 in solvents like N,N-dimethylformamide,acetonitrile, acetone or methyl-ethyl ketone in the presence of a weakbase like cesium or potassium carbonate at a temperature ranging fromroom temperature to 140° C., preferably around 50° C. to yield ethercompounds 10 (step f). Those can optionally be hydrolyzed according tostandard procedures, e.g. by treatment with an alkali hydroxide likeLiOH or NaOH in a polar solvent mixture liketetrahydrofuran/ethanol/water leading to carboxylic acids 11 (step g).If carefully controlled reaction conditions are applied as detailed inthe experimental part, hardly any racemisation occurs during thisreaction sequence. The optical purity of compounds 10 and 11 can bedetermined by chiral HPLC or by ¹H-NMR-spectroscopy in the presence of achiral solvent like 1-(9-anthryl)-2,2,2-trifluoro-ethanol and has beenfound higher than 95% in all cases exemplified.

Aldehydes 1 (prepared as outlined in scheme 5) can be reacted with aWittig salt 2 such as (1,2-diethoxy-2-oxoethyl)triphenyl phosphoniumchloride or (1,2-dimethoxy-2-oxoethyl)triphenyl phosphonium bromide insolvents like isopropanol, dichloromethane or tetrahydrofuran ormixtures thereof in the presence of a base like potassium carbonate,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,1,3,3-tetramethyl-guanidine, preferably between 0° C. and the refluxtemperature of the solvents, giving acrylic esters 3 as E and/or Zisomers (step a). Hydrogenation of acrylic esters 3 using palladium oncharcoal as catalyst, preferably at room temperature and 1 atm. pressureof hydrogen, in solvents like methanol, ethanol, tetrahydrofuran, aceticacid, dichloromethane and mixtures thereof, affords racemic esters 7,provided that the protecting group can be cleaved reductively (step e).

Alternatively, aldehydes 1 are reacted with the enolate of alkoxy-aceticacid esters 4 (preferably the lithium-enolate, prepared at −78° C. bytreatment of 4 with a strong, non-nucleophilic base like lithiumdiisopropylamide in an inert solvent like tetrahydrofuran), preferablyat temperatures around −78° C., in solvents like tetrahydrofuran givingthe aldol product 5 as a mixture of diasteromers (step b). Removal ofthe benzylic hydroxy group as described above for the conversion ofcompounds 6 to compounds 7 in scheme 1 yields racemic esters 6 (step d);ensuing removal of the protecting group, e.g. a benzyl group, can thenbe performed by standard technology as described for the conversion ofcompounds 7 to compounds 8 in scheme 1 to give phenolic compounds 7(step g). Catalytic hydrogenation can also be used to convert in onestep benzyl protected hydroxy compounds 5 into phenolic compounds 7(step f) as described for the conversion of compounds 6 to compounds 8in scheme 1. The cleavage of the protective function can also beperformed before the removal of the benzylic hydroxy group; in such acase, similar reaction conditions can be chosen for the removal of thebenzylic hydroxy group as just described for the transformation ofcompounds 5.

As an alternative method, compounds 5 can be treated with catalyticamounts of an acid like para toluene sulfonic acid in a solvent likebenzene or toluene, preferably under conditions allowing the removal ofthe water formed (e.g. with a Dean Stark trap or in the presence ofmolecular sieves) at temperatures between room temperature and thereflux temperature of the solvents to yield acrylic esters 3 (step c).

The transformation of phenolic intermediates 7 into esters 9 and/oracids 10 can be performed in perfect analogy as described for homochiralphenolic intermediates 8 in scheme 1 (steps h and i).

Homochiral alpha-alkoxy-phenyl-propionic acid esters of formula 6 andfree acids of formula 7 can also be prepared according to a linearsynthetic sequence depicted in scheme 3. Thus, reaction types alreadydescribed in scheme 1 are used in a different order beginning with thecondensation of aryl-oxazole synthons 1 (prepared as outlined in schemes6 and 7) with phenols 2 (prepared as outlined in scheme 5) affordingether compounds 3 bearing an aldehyde moiety (step a). In case R³ and/orR⁴ contain a functional group, which might not be compatible with thefollowing reaction steps, e.g. R³ and/or R⁴ might be a phenolicOH-function, then a protective group should be attached to such afunctional group, e.g. a tert-butly-dimethyl-silyl moiety. Such aprotective group can then be removed at a suitable stage later in thereaction sequence.

These ether compounds 3 are then reacted with the chiral synthons(compounds 3 in scheme 1) to form aldol-adducts 4 (step b). Removal ofthe benzylic hydroxy function in compounds 4 leads to compounds 5 (stepc), which can be converted into the corresponding esters 6 (step d) oracids 7 (step e) as described for the analogous reactions in scheme 1and 2, respectively.

Optionally, ester compounds 6 can be hydrolysed to acids 7 (step f). Theoptical purity of compounds 6 and 7 can be determined by chiral HPLC orby ¹H-NMR-spectroscopy in the presence of a chiral solvent like1-(9-anthryl)-2,2,2-trifluoro-ethanol and has been found to be higherthan 95% in all cases exemplified.

Aryl-oxazole compounds 2 (prepared as outlined in schemes 6 and 7) arecondensed with phenols 1 or aldehydes 6 (prepared as outlined in scheme5) in perfect analogy as described for homochiral phenolic intermediates8 and aryl-oxazole compounds 9 in scheme 1; thus ether compounds 3 oraldehydes 5 are obtained (step a). The former are then subjected tobromomethylation, e.g. by treatment with trioxane and HBr, preferably62% aq. HBr, in an inert solvent, preferably dichloromethane, preferablyat 0° C. giving a highly reactive, often quite unstable electrophile 4(step b). The electrophile 4 is suitable to alkylate an enolate ofalkoxy-acetic acid esters 7 (R⁶=lower alkyl), preferably thelithium-enolate, prepared at −78° C. by treatment of 7 with a strong,non-nucleophilic base like lithium diisopropylamide in an inert solventlike tetrahydrofuran, to give esters 9 (step d). To increase thereactivity of the enolate nucleophile, the reaction is preferablyperformed in the presence of a cosolvent like hexamethylphosphoramide(HMPA) or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).

Alternatively, aldehyde compounds 5, which are also available from etherintermediates 3 by Vilsmeier formylation or through formylation withdichloromethyl methyl ether in the presence of titanium tetrachloride,preferably in dichloromethane at temperatures between −78° C. and thereflux temperature of the solvent (step c), are reacted with an enolateof alkoxy-acetic acid esters 7 as described for the analogous reactionof compounds 1 and compounds 4 in scheme 2 giving the aldol products 8as a mixture of diasteromers (step e). Removal of the benzylic hydroxygroup in compounds 8 leads to racemic esters 9 (step f), as describedfor the analogous reactions in scheme 1, 2 and 3, respectively.

Alternatively, aldehydes 5 can be reacted with a Wittig salt asdescribed for the conversion of compounds 1 to compounds 3 in scheme 2giving acrylic esters 10 as E and/or Z isomers (step g). Hydrogenationof acrylic esters 10 as described for the analogous reaction in scheme 2leads to compounds 9 (step h). Hydrolysis of racemic ester compounds 9can be performed in perfect analogy as described for homochiralcompounds 10 in scheme 1 leading to carboxylic acids 11 (step i).

Aldehydes 4 (scheme 1), aldehydes 1 (scheme 2), aldehydes 2 (scheme 3),and aldehydes 6 (scheme 4) are known or can be synthesized by methodsknown in the art. Examples for possible syntheses of these keyintermediates are given in scheme 5.

Known phenols 1 can be transformed into aldehydes 3 either by knownformylation reactions such as e.g. the Vilsmeier formylation, bytreatment with hexamethylene tetramine under acidic conditions, e.g. inthe presence of sulfuric acid or, preferably, with trifluoroacetic acidas solvent between 0° C. and the reflux temperature of trifluoroaceticacid, or by formylation with dichloromethyl methyl ether in the presenceof titanium tetrachloride, preferably in dichloromethane at temperaturesbetween −78° C. and the reflux temperature of the solvent (step a);alternatively, a two step procedure might be used: introduction of ahalogen atom into the para position, e.g. by use of N-bromo- orN-iodo-succinimide, e.g. in a mixture of concentrated sulfuric acid andtetrahydrofuran preferably at ambient temperature, followed by a metalhalogen exchange, realized by treatment with an alkyl-lithium reagentlike n-butyllithium, preferably at temperatures around −78° C., andquenching the resulting aryl-Li with a formyl transfer reagent likeN,N-dimethylformamide or N-formyl-piperidine (steps b and c).Alternatively, a carbonylation reaction can be used for the introductionof the formyl group in step c, e.g. by use of sodium formate,bis(triphenylphosphine) palladium(II) dichloride and CO gas in a solventlike N,N-dimethylformamide, preferably at temperatures around 100° C.

Aldehydes 1 are commercially available or known. They are condensed withdiketo-monoximes 2 according to literature precedence (Diels, O.; Riley,K.; Chem Ber (1915), 48, 897) in the presence of a strong acid,typically HCl, in a polar solvent like AcOH to yield theoxazole-N-oxides 3 (step a). Subsequent treatment with POCl₃ indichloromethane under reflux provides the corresponding primarychlorides 4 (Goto, Y.; Yamazaki, M.; Hamana, M.; Chem Pharm Bull (1971),19, 2050, step b. The primary chlorides 4 are either used as such ortransformed according to well established methods into the correspondingprimary alcohols [e.g. with acetic acid in the presence of sodiumiodide, potassium carbonate at elevated temperature and subsequentsaponification of the acetate formed (e.g. with lithium hydroxide inethanol/water at room temperature)]. Alternatively, the primarychlorides 4 are further elaborated via S_(N)2-reaction with NaCN togive, via nitrils 5 (step c), exhaustive hydrolysis (step d) andreduction (step e), e.g. with borane in tetrahydrofuran, the buildingblocks 7. Hydroxy-ethyl compounds 7 or the hydroxymethyl compoundsprepared form primary chlorides 4 correspond to or can be converted intocompounds 9 (scheme 1), 8 (scheme 2), 1 (scheme 3) or 2 (scheme 4) e.g.by treatment with methanesulfonyl chloride in dichloromethane in thepresence of a base like triethylamine preferably in a temperature rangebetween −20° C. and room temperature or by reaction with carbontetrachloride or carbon tetrabromide and triphenylphosphine in solventslike tetrahydrofuran preferably in a temperature range between roomtemperature and the reflux temperature of the solvents; thus yieldingcompounds 9 (scheme 1), 8 (scheme 2), 1 (scheme 3) or 2 (scheme 4) asmethanesulfonates, chlorides or bromides, respectively.

4-Chloromethyl-2-aryl or 2-heteroaryl-oxazoles 4 with R² equal hydrogenare preferably prepared from the corresponding aryl or heteroarylcarboxamides and 1,3-dichloroacetone as described e.g. in Bioorg. Med.Chem. Lett. (2000), 10(17), 2041-2044.

N-Acyl-glycine esters 1 are either commercially available, known, or canbe prepared by standard operations of N-acylation. Mono-allylated esters2 can easily be obtained by double deprotonation of 1 with a strong,non-nucleophilic base like LiHMDS in an aprotic solvent like THF,typically at −78° C., followed by treatment with allyl bromide toproduce selectively the C-alkylated products 2 (step a). Standardhydrolysis generates intermediate acids 3 (step b), which are thentransformed, following well established literature precedence (J. Med.Chem. (1996), 39, 3897), into compounds 4 (step c). Ring-closure to theoxazole using trifluoro-acetic acid and trifluoro-acetic anhydride orBurgess-reagent (methyl-N-triethylammoniosulfonyl-carbamate) generateskey intermediates 5 (step d), which, finally, are elaborated viahydroboration to the target alcohols 6, e.g. with 9-BBN in THF andensuing oxidative work-up with H₂O₂ and NaOH (step e). Alcohols 6correspond to or can be converted into compounds 9 (scheme 1), 8 (scheme2), 1 (scheme 3) or 2 (scheme 4) e.g. by treatment with methanesulfonylchloride in dichloromethane in the presence of a base like triethylaminepreferably in a temperature range between −20° C. and room temperatureor by reaction with carbon tetrachloride or carbon tetrabromide andtriphenylphosphine in solvents like tetrahydrofuran preferably in atemperature range between room temperature and the reflux temperature ofthe solvents; thus yielding compounds 9 (scheme 1), 8 (scheme 2), 1(scheme 3) or 2 (scheme 4) as methanesulfonates, chlorides or bromides,respectively.

The following tests were carried out in order to determine the activityof the compounds of formula (I).

Background information on the performed assays can be found in: NicholsJ S et al. “Development of a scintillation proximity assay forperoxisome proliferator-activated receptor gamma ligand binding domain”,(1998) Anal. Biochem. 257: 112-119.

Full-length cDNA clones for human PPARα and mouse PPARγ were obtained byRT-PCR from human adipose and mouse liver cRNA, respectively, clonedinto plasmid vectors and verified by DNA sequencing. Bacterial andmammalian expression vectors were constructed to produceglutathione-s-transferase (GST) and Gal4 DNA binding domain proteinsfused to the ligand binding domains (LBD) of PPARγ (aa 174 to 476) andPPARα (aa 167 to 469). To accomplish this, the portions of the clonedsequences encoding the LBDs were amplified from the full-length clonesby PCR and then subcloned into the plasmid vectors. Final clones wereverified by DNA sequence analysis.

Induction, expression, and purification of GST-LBD fusion proteins wereperformed in E. coli strain BL21(pLysS) cells by standard methods (Ref:Current Protocols in Molecular Biology, Wiley Press, edited by Ausubelet al.).

Radioligand Binding Assay

PPARα receptor binding was assayed in TKE10 (10 mM Tris-HCl, pH 8, 50 mMKCl, 2 mM EDTA, 0.1 mg/ml fatty acid free BSA and 10 mM DTT). For each96 well 2.4 ug equivalent of GST-PPARα-LBD fusion protein andradioligand, e.g. 40000 dpm2(S)-(2-benzoyl-phenylamino)-3-{4-[1,1-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid, were incubated in 100 ul volume at RT for 2 hrs. Bound ligand wasremoved from unbound ligand by solid phase separation using MultiScreenplates (Millipore) filled with 80 ul of SG25 according to themanufacturer's recommendations.

PPARγ receptor binding was assayed in TKE50 (50 mM Tris-HCl, pH 8, 50 mMKCl, 2 mM EDTA, 0.1 mg/ml fatty acid-free BSA and 10 mM DTT). For each96 well reaction an 140 ng equivalent of GST-PPARγ-LBD fusion proteinwas bound to 10 ug SPA beads (PharmaciaAmersham) in a final volume of 50ul by shaking. The resulting slurry was incubated for 1 h at RT andcentrifuged for 2 min at 1300 g. The supernatant containing unboundprotein was removed and the semidry pellet containig the recptor-coatedbeads was resolved in 50 ul of TKE. For radioligand binding e.g. 10000dpm2(S)-(2-benzoyl-phenylamino)-3-{4-[1,1-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid in 50 ul were added, the reaction incubated at RT for 1 h andscintillation proximity counting performed. All binding assays wereperformed in 96 well plates and the amount of bound ligand measured on aPackard TopCount using OptiPlates (Packard). Nonspecific binding wasdetermined in the presence of 10⁻⁴ M unlabelled compound. Dose responsecurves were done in triplicates within a range of concentration from10⁻¹⁰ M to 10⁻⁴ M.

Luciferase Transcriptional Reporter Gene Assays

Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM mediumcontaining 10% FBS at 37° C. in a 95% O2:5% CO₂ atmosphere. Cells wereseeded in 6 well plates at a density of 10⁵ Cells/well and thentransiently batch-transfected with either the pFA-PPARγ-LBD orpFA-PPARα-LBD expression plasmids plus a reporter plasmid and anexpression plasmid encoding the secretable form of alkaline phosphatase(SEAP) as a normalization control. Transfection was accomplished withthe Fugene 6 reagent (Roche Molecular Biochemicals) according to thesuggested protocol. Six hours following transfection, the cells wereharvested by trypsinization and seeded in 96 well plates at a density of10⁴ cells/well. After 24 hours to allow attachment of cells, the mediumwas removed and replaced with 100 ul of phenol red-free mediumcontaining the test substances or control ligands (final DMSOconcentration: 0.1%). Following incubation of the cells for 24 hourswith substances, 50 ul of the supernatant was recovered and analyzed forSEAP activity (Roche Molecular Biochemicals). The remainder of thesupernatant was discarded, 50 ul PBS was added per well followed by onevolume of Luciferase Constant-Light Reagent (Roche MolecularBiochemicals) to lyse the cells and initiate the luciferase reaction.Luminescence for both SEAP and luciferase was measured in a PackardTopCount. Luciferase activity was normalized to the SEAP control andtranscriptional activation in the presence of a test substance wasexpressed as fold-activation over cells incubated in the absence of thesubstance. EC50 values were calculated using the XLfit program (IDBusiness Solutions Ltd. UK).

The free acids of the compounds of the present invention (R⁶ ishydrogen) exhibit IC₅₀ values of 0.1 nM to 50 μM, preferably 1 nM to 10μM for PPARα and PPARγ. The compounds further exhibit EC₅₀ values of 0.1nM to 50 μM, preferably 1 nM to 10 μM for PPARα and PPARγ. Compounds, inwhich R⁶ is not hydrogen are converted in vivo to compounds in which R⁶is hydrogen. The following table shows measured values for some selectedcompounds of the present invention and for a compound already known inthe art (e.g.: Rosiglitazone, Drugs 1999, Vol 57(6), 921-930).

PPARα PPARγ PPARα PPARγ IC₅₀ IC₅₀ EC₅₀ EC₅₀ Example 2  30 nmol/l  58nmol/l 163 nmol/l 115 nmol/l Example 3  87 nmol/l  506 nmol/l  57 nmol/l 87 nmol/l Example 5  155 nmol/l  146 nmol/l  38 nmol/l 124 nmol/lExample 9  196 nmol/l  129 nmol/l  21 nmol/l  33 nmol/l Example 17  73nmol/l  31 nmol/l 186 nmol/l 174 nmol/l Example 23  52 nmol/l  48 nmol/l306 nmol/l 138 nmol/l Example 25  177 nmol/l  129 nmol/l  26 nmol/l  75nmol/l Example 29 2380 nmol/l 1730 nmol/l 213 nmol/l 678 nmol/l Example37  74 nmol/l  318 nmol/l  14 nmol/l  12 nmol/l Example 43  131 nmol/l 33 nmol/l 150 nmol/l  57 nmol/l Rosiglitazone inactive 1090 nmol/linactive 405 nmol/l

The compounds of formula (I) and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula (I) and theirpharmaceutically acceptable, into a galenical administration formtogether with suitable, non-toxic, inert, therapeutically compatiblesolid or liquid carrier materials and, if desired, usual pharmaceuticaladjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules).

Suitable carrier materials for the production of solutions and syrupsare, for example, water, polyols, sucrose, invert sugar and the like.Suitable carrier materials for injection solutions are, for example,water, alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 0.1 mg to about 1000mg, especially about 0.1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.05-500 mg,preferably 0.05-100 mg of a compound of formula (I).

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

Abbreviations:

AcOEt=ethyl acetate, AcOH=acetic acid, nBu₂BOTf=dibutylboron triflate,n-BuLi=n-butyllithium, DBAD=di-tert-butyl azodicarboxylate,DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DEAD=diethyl azodicarboxylate,DIAD=diisopropyl azodicarboxylate,DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,eq.=equivalents, h=hour(s), HPLC=high performance liquid chromatography,LDA=lithium diisopropylamide, min=minute(s), POCl₃=phosphorousoxychloride, THF=tetrahydrofuran.

Example 1 a](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

(S)-4-Benzyl-3-ethoxyacetyl-oxazolidin-2-one (12.45 g, 47 mmol) (for thepreparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D.Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C.Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron:Asymmetry 1999, 10, 1353-1367) was dissolved in dry dichloromethane (270ml) under an argon atmosphere and the solution was cooled to −78° C.Triethylamine (7.98 ml, 57 mmol) was added, followed by the slowaddition, over approximately 20 min, of di-n-butylboron triflate (1 Msolution in dichloromethane, 50 ml, 50 mmol) such that the reactiontemperature was kept below −70° C. The mixture was stirred at −78° C.for 50 min, the cooling bath was replaced with an ice bath and themixture stirred at 0° C. for additional 50 min before being recooled to−78° C. A solution of 4-benzyloxy-2-methyl-benzaldehyde (10.7 g, 47mmol) in dry dichloromethane (130 ml) was added over ca. 45 min, suchthat the reaction temperature was maintained below −70° C. The resultingmixture was stirred at −78° C. for 45 min, warmed from −78° C. to 0° C.and stirred at 0° C. for a further 1.5 h. The reaction mixture waspoured onto ice water/brine and extracted two times withdichloromethane. The combined extracts were washed with brine and driedover sodium sulfate. The solvent was removed under reduced pressure andthe residue purified by column chromatography (silica gel,cyclohexane/AcOEt) to give 22.3 g (45.6 mmol, 96%) of the title compoundas colorless oil. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 512.3 (M+Na)⁺, 472.3, 447.2, 387.2, 327.2, 295.3, 267.3, 232.1,175.1.

b] (2S,3R)-3-(4-Benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

A 5.4 M solution of sodium methoxide (7.3 ml, 39.5 mmol) was added to anice-cooled and stirred suspension of(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one(17.6 g, 36 mmol) in dry methanol (87 ml). The mixture was stirred at 0°C. for 15 min, quenched and neutralized by the addition of diluteaqueous hydrochloric acid (1.0 M). The solution was concentrated underreduced pressure and the residue dissolved in ice water/ethyl acetate1/1. The layers were separated and the aqueous layer was extracted twotimes with ethyl acetate. The combined organic layers were washed withice water and dried over sodium sulfate. The solvent was removed underreduced pressure and the residue purified by column chromatography(silica gel, cyclohexane/AcOEt) to give 8.6 g (25 mmol, 69%) of thetitle compound as light yellow oil. According to ¹H-NMR spectroscopy,one single diastereomer was obtained.

MS: 367.2 (M+Na)⁺, 362.2 (M+NH₄)⁺, 327.3, 299.3, 239.3, 211.2.

c] (2S)-3-(4-Benzyloxy-2-methyl-phenyl)-2-ethoxy-propionic acid methylester

Triethylsilane (23 ml, 145 mmol) was added to a vigorously stirred,ice-cooled solution of(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester (5 g, 14.5 mmol) in trifluoroacetic acid (84 ml) underan argon atmosphere. The mixture was stirred at 0° C. for 30 min and foradditional 2 h at ambient temperature. The solution was poured ontocrashed ice and extracted with ethyl acetate. The organic layer waswashed two times with water and neutralized with saturated aqueoussodium bicarbonate solution. The ethyl acetate layer was washed withbrine and dried over sodium sulfate. The solvent was removed underreduced pressure to give a colorless oil which was purified by columnchromatography (silica gel, cyclohexane/AcOEt) to yield 2.15 g (6.5mmol, 45%) of the title compound as colorless oil.

MS: 351.2 (M+Na)⁺, 346.3 (M+NH₄)⁺, 283.2, 276.2, 223.2, 195.5.

d] (2S)-2-Ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methylester

A solution of (2S)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-propionicacid methyl ester (3.6 g, 11 mmol) in methanol (300 ml) was hydrogenatedover 10% palladium on charcoal (1 g) at ambient temperature for 2 h. Thecatalyst was filtered off and the solvent evaporated under reducedpressure to give 2 g (8.4 mmol, 77%) of the title compound as yellowliquid which was used in the next step without further purification.

MS: 261.2 (M+Na)⁺, 256.1 (M+NH₄)⁺, 239.3 (M+H)⁺, 193.2, 151.1.

e] 4-Chloromethyl-5-methyl-2-o-tolyl-oxazole

2-Methyl-benzaldehyde (19.3 ml, 166 mmol) was dissolved in acetic acid(175 ml) and treated with diacetyl monooxime (16.8 g, 166 mmol). Astream of dry HCl was bubbled for 2 h at 0° C. and for additional 2 h atambient temperature through the solution (slightly exothermic). Thereaction mixture was poured onto ice water and extracted two times withdichloromethane. The combined extracts were washed with water, saturatedaqueous sodium bicarbonate solution (until a pH of 8 was adjusted) andbrine. The organic layer was dried over sodium sulfate and the solutionwas concentrated to a volume of approximately 100 ml under reducedpressure. Chloroform (200 ml) was added and the solution was brought toa volume of approximately 100 ml under reduced pressure. Chloroform (100ml) was added and the solution of crude 4,5-dimethyl-2-o-tolyl-oxazole3-oxide was cooled to 0° C. A solution of phosphorous oxychloride (16.7ml, 183 mmol) in chloroform (175 ml) was added within 10 min. Thereaction mixture was heated under reflux for 12 h, cooled to 0° C. andmade basic (pH 10) by carefully adding concentrated aqueous NH₃solution. The suspension was poured onto ice water and extracted twotimes with dichloromethane. The combined extracts were washed with icewater/brine and dried over sodium sulfate. Removal of the solvent underreduced pressure gave a yellow oil which was purified by columnchromatography (silica gel, cyclohexane/AcOEt) to yield 29 g (131 mmol,79%) of the title compound as yellow oil, which solidified uponstanding.

MS: 221.1 (M)⁺, 186.1, 118.0, 89.0, 43.1.

f](S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

A mixture of (S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acidmethyl ester (80 mg, 0.34 mmol),4-chloromethyl-5-methyl-2-o-tolyl-oxazole (82 mg, 0.37 mmol), cesiumcarbonate (120 mg, 0.37 mmol) and a trace of potassium iodide weresuspended in acetone (8 ml). The suspension was heated under reflux for5 h, the solvent evaporated under reduced pressure and the residuedissolved in 2 N HCl/ice water 1/1 and ethyl acetate. The layers wereseparated and the aqueous layer was extracted two times with ethylacetate. The combined organic layers were washed two times with brineand dried over sodium sulfate. The solvent was removed under reducedpressure and the residue purified by column chromatography (silica gel,cyclohexane/AcOEt) to give 100 mg (0.24 mmol, 70%) of the title compoundas yellow oil.

MS: 446.2 (M+Na)⁺, 424.3 (M+H)⁺, 345.1, 269.2, 229.2, 215.4, 186.3.

g](S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

To a solution of(S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester (100 mg, 0.24 mmol) in THF/methanol 2/1 (1.5 ml) wasadded a 1 N aqueous LiOH solution (1.4 ml, 1.4 mmol). The reactionmixture was stirred for 1.5 h at ambient temperature, neutralized with 1N aqueous HCl solution under ice cooling and concentrated under reducedpressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethylacetate, the layers were separated and the aqueous layer was extractedwith ethyl acetate. The combined organic layers were washed with icewater/brine 1/1, dried over sodium sulfate and the solvent wasevaporated in vacuo to give the title compound (88 mg, 0.21 mmol, 91%)as off-white solid, which was crystalized from dichloromethane/hexane toafford colorless crystals. According to chiral HPLC of the correspondingmethyl ester (Chiralcel-ODH), the enantiomeric excess amounts to 98.6%.

MS: 408.5 (M−H)⁻, 362.3, 305.4, 280.9, 255.1, 216.6.

Example 1a a]3-(4-Benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethylester (mixture of stereoisomers)

To a −78° C. cold 2 M solution of lithium diisopropylamide (305 mmol) inTHF/n-heptane (152.4 ml) was added a solution of ethoxy-acetic acidethyl ester (45.2 ml, 331 mmol) in tetrahydrofuran (240 ml) within 1.5 hunder an argon atmosphere. The mixture was stirred for 30 min. Asolution of 4-benzyloxy-2-methyl-benzaldehyde (30 g, 132.6 mmol) intetrahydrofuran (420 ml) was added dropwise over a period of 50 min. Thereaction mixture was stirred 2 h at −78° C., poured onto icewater/aqueous ammonium chloride solution 1/1 and extracted two timeswith ethyl acetate. The combined extracts were washed three times withice water/brine 1/1 and dried over sodium sulfate. The solvent wasremoved under reduced pressure and the residue purified by columnchromatography (silica gel, n-heptane/AcOEt) to give 48.8 g (136.2 mmol)of the title compound as a mixture of stereoisomers as yellow oil.

MS: 376.4 (M+NH₄)⁺, 341.4, 186.5.

b] (Z)-3-(4-Benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylic acid ethyl ester

To a solution of3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethylester (mixture of stereoisomers; 48.8 g, 136.2 mmol) inN,N-dimethylformamid (500 ml) was added sulfuric acid (19.6 ml, 96%).The reaction mixture was heated to 100° C. for 2.5 h, cooled to ambienttemperature, poured onto ice water/saturated aqueous NaHCO₃ solution 1/1and extracted two times with ethyl acetate. The combined extracts werewashed with ice water/brine 1/1 and dried over sodium sulfate. Thesolvent was removed under reduced pressure to give 46.1 g (135.4 mmol)of crude (Z)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylic acid ethylester which was used in the next step without further purification.

MS: 358.3 (M+NH₄)⁺, 341.4 (M+H)⁺, 292.4, 222.4, 187.4.

c] (Z)-2-Ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester

To a solution of (Z)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylicacid ethyl ester (46.1 g, 135.4 mmol) in dichloromethane (500 ml) wasadded BF3.OEt₂ (186 ml, 677 mmol, 46%) and dimethyl sulfide (149 ml,2.03 mol). The reaction mixture was stirred at ambient temperature for14 h, poured onto ice water and extracted two times withdichloromethane. The combined extracts were washed with ice water/brine1/1 and dried over sodium sulfate. The solvent was removed under reducedpressure and the residue purified by column chromatography (silica gel,n-heptane/AcOEt) to give 23.1 g (92.3 mmol, 68% over three steps) of thetitle compound as yellow crystals.

MS: 248.9 (M+H)⁻, 219.9.

d](Z)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester

In analogy to the procedure described in example 1 f],(Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester wasreacted with 4-chloromethyl-5-methyl-2—o— tolyl-oxazole (example 1 f])in the presence of cesium carbonate and potassium iodide to yield(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester as colorless crystals.

MS: 458.4 (M+Na)⁺, 436.4 (M+H)⁺, 291.5, 187.5.

e](Z)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid

To a solution of(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester (6.8 g, 15.6 mmol) in THF/methanol 2/1 (102 ml) wasadded a 3 M aqueous NaOH solution (26 ml, 78 mmol). The reaction mixturewas stirred for 3 h at ambient temperature, concentrated under reducedpressure, diluted with ice water and acidified with with 1 M aqueous HClsolution. Twofold extraction with ethyl acetate was followed by washingof the combined extracts with ice water/brine 1/1 (three times) anddrying of the organic layer over sodium sulfate. The solvent was removedunder reduced pressure and the crude product crystallized fromdichloromethane/n-heptane to give the title compound (6.3 g, 15.5 mmol,99%) as colorless crystals.

MS: 406.3 (M−H)⁻, 334.2, 255.2.

f](S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 6a c],(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid was hydrogenated for 16 h at 60 bar of hydrogen at 40° C. indichloromethane/methanol/30% aqueous NaOH solution 1/1/0.04 using[Ru(OAc)₂((+)-TMBTP)] catalyst to yield after work-up a black solid withan enantiomeric purity of 93% and a chemical purity of >99% according toHPLC. The crude product was purified by column chromatography (silicagel, n-heptane/AcOEt/AcOH, two times) to give brown crystals which wererecrystallized from ethyl acetate to afford the title compound asoff-white crystals. According to chiral HPLC (Chiralcel-ODH column, 25cm×4.6 mm, 97% heptane/3% iso-propanol with 0.15% trifluoroacetic acid,flow at 0.8 ml/min, 25° C., 274 nm. Retention times: R-acid 19.3 min,S-acid 21.6 min, α,β-unsaturated Z-acid 28.2 min), the enantiomericexcess amounts to 99.8%.

MS: 408.3 (M−H)⁻, 362.2.

Example 2 a] 2-(4-Isopropoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide;hydrochloride

Into a suspension of diacetyl monooxime (1 g, 9.9 mmol) and4-isopropoxy-benzaldehyde (1.6 g, 9.9 mmol) in acetic acid (10 ml), dryhydrogen chloride was bubbled for 30 min under ice-cooling and foradditional 45 min at ambient temperature. The reaction mixture wascooled to 0° C., diethyl ether (25 ml) was added within 5 min and theformed precipitate was filtered off and washed with ice-cold diethylether to yield the title compound (2.5 g, 8.8 mmol, 89%) as colorlesscrystals.

MS: 247.2 (M−HCl)⁺, 205.1, 188.1, 121.2, 93.2, 43.3.

b] 4-Chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole

To a solution of 2-(4-isopropoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide;hydrochloride (2.5 g, 8.8 mmol) in chloroform (12 ml) was added asolution of phosphorous oxychloride (1 ml, 11 mmol) in chloroform (12ml) within 5 min. The reaction mixture was heated under reflux for 45min, cooled to 0° C. and made basic (pH 10) by carefully addingconcentrated aqueous NH₃ solution. The suspension was poured onto icewater and extracted two times with dichloromethane. The combinedextracts were washed with ice water/brine and dried over sodium sulfate.Removal of the solvent under reduced pressure gave a brown oil which waspurified by column chromatography (silica gel, dichloromethane) to yield1.6 g (6 mmol, 60%) of the title compound as colorless oil.

MS: 266.3 (M+H)⁺, 224.2, 188.3.

c](S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(example 1 d]) was reacted with4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole in the presenceof cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 490.2 (M+Na)⁺, 468.2 (M+H)⁺, 269.2, 230.2, 188.3.

d](S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid as colorless solid.

MS: 452.3 (M−H)⁻, 343.0, 283.3, 246.8, 218.7.

Example 3 a](S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(example 1 d]) was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazolein the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 432.3 (M+Na)⁺, 410.3 (M+H)⁺, 293.2, 269.2, 187.2, 172.2.

b](S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless solid, which was crystalized fromhexane/dichloromethane to afford colorless crystals. According to chiralHPLC of the corresponding methyl ester (Chiralcel-OJ), the enantiomericexcess amounts to 99.0%.

MS: 394.2 (M−H)⁻, 348.2, 293.2, 223.1.

Example 3a a](Z)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester

In analogy to the procedure described in example 1 f],(Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester(example 1a c]) was reacted with4-chloromethyl-5-methyl-2-phenyl-oxazole (example 3 a]) in the presenceof cesium carbonate and potassium iodide to yield(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester as colorless solid.

MS: 444.3 (M+Na)⁺, 422.5 (M+H)⁺, 267.5, 213.5.

b](Z)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid

In analogy to the procedure described in example 1a f],(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester was treated with NaOH to obtain(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid as colorless solid.

MS: 394.3 (M+H)⁺, 279.3, 249.3.

c](S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 6a c],(Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid was hydrogenated in a 35 ml autoclave for 16 h at a hydrogenpressure of 60 bar at 40° C. in dichloromethane/methanol/30% aqueousNaOH solution 1/1/0.03 using [Ru(OAc)₂((+)-TMBTP)] catalyst to yieldafter work-up a black solid with an enantiomeric purity of 93% and achemical purity of >99% according to HPLC. The crude product waspurified by column chromatography (silica gel, n-heptane/AcOEt/AcOH, twotimes) to give brown crystals which were recrystallized from ethylacetate to afford the title compound as colorless crystals. According tochiral HPLC (Chiralcel-OJH column, 25 cm×4.6 mm, 80% heptane/20% ethanolwith 1.5% trifluoroacetic acid, flow at 0.8 ml/min, 25° C., 275 nm.Retention times: R-acid 26.4 min, S-acid 29.1 min, α,β-unsaturatedZ-acid 32.6 min), the enantiomeric excess amounts to 99.2%.

MS: 394.2 (M−H)⁻, 348.2.

Example 4 a](S)-3-{4-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(example 1 d]) was reacted with4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole (prepared from3,5-dimethoxy-benzaldehyde and diacetyl monoxyme followed by treatmentwith POCl₃ in analogy to the procedures described in examples 2 a] andb]) in the presence of cesium carbonate and potassium iodide to yield(S)-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 492.2 (M+Na)⁺, 470.1 (M+H)⁺, 273.2, 232.1, 205.2, 164.2.

b](S)-3-{4-[2-(3,5-Dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid as colorless solid.

MS: 454.3 (M−H)⁻, 408.2, 364.1, 305.0, 255.0, 223.1.

Example 5 a] 2-(4-Fluoro-3-methyl-phenyl)-4,5-dimethyl-oxazole 3-oxide

Into a suspension of diacetyl monooxime (11 g, 108.6 mmol) and4-fluoro-3-methyl-benzaldehyde (15 g, 108.6 mmol) in acetic acid (100ml), dry hydrogen chloride was bubbled for 30 min under ice-cooling andfor additional 45 min at ambient temperature. The reaction mixture waspoured onto ice water and extracted two times with ethyl acetate. Thecombined extracts were washed with ice water, saturated aqueous sodiumbicarbonate solution (until a pH of 8 was adjusted) and brine. Theorganic layer was dried over sodium sulfate and the solvent removedunder reduced pressure to afford the title compound (12.3 g, 55.6 mmol,51%) as yellow crystals.

MS: 222.1 (M+H)⁺, 205.1, 176.1, 137.1, 109.1.

b] 4-Chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole

In analogy to the procedure described in example 2 b],2-(4-fluoro-3-methyl-phenyl)-4,5-dimethyl-oxazole 3-oxide was treatedwith phosphorous oxychloride in chloroform to yield4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole ascolorless solid.

MS: 239.0 (M)⁺, 204.1, 136.1, 43.2.

c](S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(example 1 d]) was reacted with4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole in thepresence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 464.2 (M+Na)⁺, 442.2 (M+H)⁺, 349.1, 317.0, 280.2, 245.2, 204.1.

d](S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid as colorless solid.

MS: 426.1 (M−H)⁻, 348.4, 263.2, 174.8.

Example 6 a](S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester(example 1 d]) was reacted with4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 450.2 (M+Na)⁺, 428.3 (M+H)⁺, 368.0, 231.2, 190.3.

b](S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid as colorless solid, which was crystalized fromhexane/dichloromethane to afford colorless crystals. According to chiralHPLC of the corresponding methyl ester (Chiralcel-ODH), the enantiomericexcess amounts to 99.4%.

MS: 412.3 (M−H)⁻, 366.5, 278.4, 254.9, 223.1.

Example 6a a](Z)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylicacid ethyl ester

In analogy to the procedure described in example 1 f],(Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester(example 1a c]) was reacted with4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (example 6 a]) inthe presence of cesium carbonate and potassium iodide to yield(Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylicacid ethyl ester as colorless crystals.

MS: 462.4 (M+Na)⁺, 440.4 (M+H)⁺, 206.4.

b](Z)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylicacid

In analogy to the procedure described in example 1a f],(Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylicacid ethyl ester was treated with NaOH to obtain(Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylicacid as colorless solid.

MS: 412.4 (M+H)⁺.

c](S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In a glove box (O₂ content≦2 ppm), a 185 ml stainless steel autoclavewas charged with 11.5 g of(Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylicacid (28.0 mmol), 35 ml of dichloromethane, 35 ml of methanol, 2.5 ml ofa 30% aqueous NaOH solution (14.0 mmol) and 22.6 mg (0.028 mmol) of[Ru(OAc)₂((+)-TMBTP)]. TMBTP is4,4′-Bis(diphenylphosphino)-2,2′,5,5′-tetramethyl-3,3′-dithiophene, itssynthesis as (R) or (S) enantiomer is described in WO 96/01831 appl toItalfarmaco Sud and in T. Benincori et al, J. Org. Chem. 2000, 65, 2043.The complex [Ru(OAc)₂((+)-TMBTP)] has been synthesized in analogy to ageneral procedure reported in N. Feiken et al, Organometallics 1997, 16,537, ³¹P-NMR (CDCl₃): δ1.4 ppm (s). The autoclave was sealed and thehydrogenation was run under stirring at 40° C. under 60 bar of hydrogen.After 16 h the autoclave was opened and the yellow-brown solution wasrotary evaporated to dryness (50° C./5 mbar). The residue was dissolvedin 60 ml of ethyl acetate, 60 ml of water and 3 ml of aqueoushydrochloric acid (25%). The organic layer was separated and evaporatedto dryness (50° C./5 mbar) to afford 12 g of crude product as a solidwith an enantiomeric purity of 92% and a chemical purity of >99%according to HPLC. The crude product was dissolved in dichloromethane,(S)-phenylethylamine (4.12 ml, 31.1 mmol) was added and the solventremoved under reduced pressure. The brown residue was crystallized fromethyl acetate to obtain colorless crystals which were suspended in icewater/ethyl acetate 1/1. The pH of the suspension was adjusted to 1 with1 M aqueous hydrochloric acid, the layers were separated and the aqueouslayer extracted two more times with ethyl acetate. The combined extractswere washed with ice water/brine 1/1, dried over sodium sulfate and thesolvent removed in vacuo to obtain colorless crystals which wererecrystallized from ethyl acetate to afford 8.45 g (20.4 mmol, 73%) ofthe title compound as colorless crystals. According to chiral HPLC(Chiralcel-ODH column, 25 cm×4.6 mm, 97% heptane/3% iso-propanol with0.15% trifluoroacetic acid, flow at 0.7 ml/min, 25° C., 274 nm.Retention times: R-acid 30.2 min, S-acid 32.8 min, α,β-unsaturatedZ-acid 39.1 min), the enantiomeric excess amounts to 100%.

MS: 412.0 (M−H)⁻.

Example 7 a](S)-4-Benzyl-3-[(2S)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 c],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one(example 1 a]) was treated with triethylsilane in trifluoroacetic acidto yield the title compound as colorless liquid.

MS: 496.2 (M+Na)⁺, 491.3 (M+NH₄)⁺, 474.2 (M+H)⁺, 428.3, 352.3, 251.2,175.2.

b](S)-4-Benzyl-3-[(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 d],(S)-4-benzyl-3-[(2S)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-propionyl]-oxazolidin-2-onewas hydrogenated over 10% palladium on charcoal to give the titlecompound as yellow liquid.

MS: 382.1 (M−H)⁻, 324.9, 305.1, 282.9, 261.8, 255.2, 221.4, 175.6.

c](S)-4-Benzyl-3-[(2S)-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionyl]-oxazolidin-2-one

To a ice cold solution of(S)-4-benzyl-3-[(2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionyl]-oxazolidin-2-one(100 mg, 260 μmol), 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol(93 mg, 390 μmol) (prepared from methyl 3-oxopentanoate and4-chloro-benzamide in analogy to the sequence described for thesynthesis of 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol in M. Scalone,PCT WO 01/79202 A1) and triphenylphosphine (103 mg, 390 mmol) intetrahydrofuran (2.5 ml) was added diethyl azodicarboxylate (61 μl, 390μmol). The cooling bath was removed and stirring was continued for 12 h.Evaporation of the solvent under reduced pressure gave a yellow oilwhich was purified by column chromatography (silica gel,cyclohexane/AcOEt) to give 70 mg (120 μmol, 45%) of the title compoundas colorless oil.

MS: 626.3 (M+Na)⁺, 603.2 (M)⁺, 557.2, 479.3, 381.2, 351.1, 273.2, 187.2.

d](S)-3-(4-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionicacid

(S)-4-Benzyl-3-[(2S)-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionyl]-oxazolidin-2-one(70 mg, 120 μmol) was dissolved in ice-cooled THF (0.7 ml) and treatedwith 1 N NaOH (0.3 ml, 300 mmol) at 0° C. for 2 h. The reaction mixturewas poured onto ice water, extracted two times with diethyl ether andthe combined organic layers were washed with ice water. The combinedaqueous layers were acidified with 1 N HCl and extracted two times withethyl acetate. The combined extracts were washed with brine and driedover sodium sulfate. Evaporation of the solvent gave 47 mg (110 mmol,91%) of the title compound as yellow liquid.

MS: 442.1 (M−H)⁻, 396.1, 362.0, 223.6, 176.4.

Example 8 a] 1-Ethyl-3-(phenylmethoxy)-benzene

To a suspension of potassium carbonate (17 g, 123 mmol) inN,N-dimethylformamide (40 ml) was added a solution of 3-ethyl-phenol(14.8 ml, 123 mmol) in N,N-dimethylformamide (40 ml) at 2° C. under anargon atmosphere. After stirring for 50 min at 2° C., benzyl bromide(14.6 ml, 123 mmol) was added over a period of 15 min at 2° C. Thesuspension was stirred for additional 30 min at 2° C. and for 12 h atambient temperature. After adding ice water (250 ml), the solution wasextracted two times with diethyl ether. The combined extracts werewashed two times with brine and dried over sodium sulfate. Evaporationof the solvent gave a yellow oil which was purified by columnchromatography (silica gel, cyclohexane) to yield 24.3 g (114 mmol, 93%)of the title compound as yellow liquid.

MS: 212.2 (M+H)⁺, 183.1, 91.2, 65.1.

b] 1-Bromo-2-ethyl-4-(phenylmethoxy)-benzene

To a solution of 1-ethyl-3-(phenylmethoxy)-benzene (15 g, 71 mmol) inTHF (200 ml) were added N-bromosuccinimide (16.3 g, 92 mmol) andconcentrated sulfuric acid (2.4 ml). The solution was stirred for 5 h atambient temperature. Sodium bicarbonate (3.6 g) and 10% aqueous NaHSO₃solution (400 ml) were added under ice cooling. The resulting mixturewas stirred for 10 min and then poured into ethyl acetate. The phaseswere separated and the aqueous phase was extracted with ethyl acetate.The combined extracts were washed with ice water and brine and driedover sodium sulfate. Removal of the solvent under reduced pressure gavea yellow oil which was purified by column chromatography (silica gel,cyclohexane) to yield 17.1 g (58.7 mmol, 83%) of the title compound ascolorless liquid.

MS: 292.0 (M)⁺, 290.0 (M)⁺, 212.2, 91.1, 65.2.

c] 4-Benzyloxy-2-ethyl-benzaldehyde

A 1.6 M solution of n-BuLi in hexane (44.4 ml, 69.9 mmol) was addedwithin 10 min to a stirred cooled (−85° C.) solution of1-bromo-2-ethyl-4-(phenylmethoxy)-benzene (18.5 g, 63.5 mmol) in dry THF(22 ml). The mixture was stirred for 1 h at −85° C. under an argonatmosphere. N,N-Dimethylformamide (25.5 ml, 330.4 mmol) was added andthe temperature was allowed to rise slowly to room temperature. Anaqueous saturated NH₄Cl solution (70 ml) was added under ice cooling.The mixture was extracted two times with dichloromethane, the combinedextracts were washed with brine and dried over sodium sulfate. Removalof the solvent under reduced pressure gave a yellow oil which waspurified by column chromatography (silica gel, cyclohexane/AcOEt) toyield 11.9 g (49.5 mmol, 78%) of the title compound as yellow oil.

MS: 240.1 (M+H)⁺, 91.1, 77.1, 65.2.

d](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 a],(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C.Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M.Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10,1353-1367) was reacted with 4-benzyloxy-2-ethyl-benzaldehyde in thepresence of triethylamine and di-n-butylboron triflate to give(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-oneas yellow foam. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 526.3 (M+Na)⁺, 521.3 (M+NH₄)⁺, 486.2, 381.2, 309.2, 281.2, 253.3,178.1.

e] (2S,3R)-3-(4-Benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

In analogy to the procedure described in example 1 b],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-onewas treated with sodium methoxide in methanol to give(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acidmethyl ester as colorless liquid. According to ¹H-NMR spectroscopy, onesingle diastereomer was obtained.

MS: 381.2 (M+Na)⁺, 376.3 (M+NH₄)⁺, 341.3, 295.3, 253.2, 225.3.

f] (2S)-3-(4-Benzyloxy-2-ethyl-phenyl)-2-ethoxy-propionic acid methylester

In analogy to the procedure described in example 1 c],(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acidmethyl ester was treated with triethylsilane in trifluoroacetic acid toyield (2S)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-propionic acid methylester as colorless liquid.

MS: 365.2 (M+Na)⁺, 360.2 (M+NH₄)⁺, 297.3, 283.2, 237.2, 209.3, 181.2.

g] (2S)-2-Ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methylester

In analogy to the procedure described in example 1 d],(2S)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-propionic acid methyl esterwas hydrogenated over 10% palladium on charcoal to give(2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl esteras colorless liquid.

MS: 275.2 (M+Na)⁺, 270.3 (M+NH₄)⁺, 253.3 (M+H)⁺, 207.2, 175.2, 165.3,147.2.

h](S)-2-Ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl esterwas reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in thepresence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 446.3 (M+Na)⁺, 424.3 (M+H)⁺, 378.3, 213.3, 172.3.

i](S)-2-Ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless foam.

MS: 408.2 (M−H)⁻, 362.0, 318.2, 236.7, 190.0.

Example 9 a](S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester(example 8 g]) was reacted with4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (example 5b]) in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 478.3 (M+Na)⁺, 456.3 (M+H)⁺, 371.3, 271.3, 245.3, 204.2.

b](S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless solid.

MS: 440.3 (M−H)⁻, 393.9, 350.1, 255.2, 237.4, 203.6.

Example 10 a](S)-2-Ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester(example 8 g]) was reacted with4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 464.2 (M+Na)⁺, 459.3 (M+NH₄)⁺, 442.2 (M+H)⁺, 396.2, 231.2, 190.3.

b](S)-2-Ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless liquid.

MS: 450.2 (M+Na)⁺, 428.3 (M+H)⁺, 382.2, 231.2, 190.3.

Example 11 a](S)-2-Ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester(example 8 g]) was reacted with4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1 e]) in the presenceof cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 460.2 (M+Na)⁺, 438.3 (M+H)⁺, 407.2, 227.2, 186.3.

b](S)-2-Ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless liquid.

MS: 446.2 (M+Na)⁺, 424.3 (M+H)⁺, 372.4, 230.2, 186.3.

Example 12 a](S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester(example 8 g]) was reacted with4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 504.4 (M+Na)⁺, 482.4 (M+H)⁺, 271.2, 230.2, 188.3.

b](S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless liquid.

MS: 490.2 (M+Na)⁺, 468.2 (M+H)⁺, 416.1, 371.4, 323.3, 271.3, 230.2,188.3.

Example 13 a] 1-Bromo-2-fluoro-4-(phenylmethoxy)-benzene

In analogy to the procedure described in example 8 b],1-fluoro-3-(phenylmethoxy)-benzene (for the preparation of1-fluoro-3-(phenylmethoxy)-benzene see: A. A. Durrani, J. H. P. Tyman,J. Chem. Soc., Perkin Trans. 1 1979, 8, 2079-2087) was treated withN-bromosuccinimide in the presence of concentrated sulfuric acid to give1-bromo-2-fluoro-4-(phenylmethoxy)-benzene as colorless oil.

b] 4-Benzyloxy-2-fluoro-benzaldehyde

In analogy to the procedure described in example 8 c],1-bromo-2-fluoro-4-(phenylmethoxy)-benzene was treated with n-BuLi andN,N-dimethylformamide in dry tetrahydrofuran to yield4-benzyloxy-2-fluoro-benzaldehyde as off-white crystals.

MS: 230.1 (M)⁺, 91.0, 65.2.

c](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 a],(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C.Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M.Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10,1353-1367) was reacted with 4-benzyloxy-2-fluoro-benzaldehyde in thepresence of triethylamine and di-n-butylboron triflate to give(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-oneas colorless foam. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 516.2 (M+Na)⁺, 476.2, 435.3, 419.3, 387.1, 330.2, 279.1, 227.2,203.1.

d] (2S,3R)-3-(4-Benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

In analogy to the procedure described in example 1 b],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-onewas treated with sodium methoxide in methanol to give(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester as colorless liquid. According to ¹H-NMR spectroscopy,one single diastereomer was obtained.

MS: 371.3 (M+Na)⁺, 331.3, 303.2, 279.2, 242.2.

e] (2S)-3-(4-Benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionic acid methylester

In analogy to the procedure described in example 1 c],(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester was treated with triethylsilane in trifluoroaceticacid to yield (2S)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 355.2 (M+Na)⁺, 350.3 (M+NH₄)⁺, 333.3 (M+H)⁺, 287.2, 273.3, 245.3.

f] (2S)-2-Ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methylester

In analogy to the procedure described in example 1 d],(2S)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-propionic acid methylester was hydrogenated over 10% palladium on charcoal to give(2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl esteras colorless liquid.

MS: 265.2 (M+Na)⁺, 260.2 (M+NH₄)⁺, 243.3 (M+H)⁺, 197.1, 183.2, 155.3.

g](S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl esterwas reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in thepresence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 436.2 (M+Na)⁺, 414.2 (M+H)⁺, 354.4, 213.3, 172.3.

h](S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless solid.

MS: 422.2 (M+Na)⁺, 400.4 (M+H)⁺, 304.0, 269.2, 241.3, 213.3, 187.3,172.3.

Example 14 a](S)-2-Ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester(example 13 f]) was reacted with4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 454.3 (M+Na)⁺, 449.3 (M+NH₄)⁺, 432.4 (M+H)⁺, 371.4, 304.2, 269.0,231.3.

b](S)-2-Ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless liquid.

MS: 416.2 (M−H)⁻, 370.1, 326.2, 255.3, 227.2.

Example 15 a](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 a],(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C.Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M.Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10,1353-1367) was reacted with 4-benzyloxy-2-chloro-benzaldehyde (for thepreparation of 4-benzyloxy-2-chloro-benzaldehyde see: T. Kimachi, M.Kawase, S. Matsuki, K. Tanaka, F. Yoneda, J. Chem. Soc., Perkin Trans. 11990, 253-256) in the presence of triethylamine and di-n-butylborontriflate to give(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-oneas colorless liquid. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 532.3 (M+Na)⁺, 527.2 (M+NH₄)⁺, 446.1, 381.2, 315.1, 287.2, 243.2,178.2.

b] (2S,3R)-3-(4-Benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

In analogy to the procedure described in example 1 b],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-onewas treated with sodium methoxide in methanol to give(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester as colorless liquid. According to ¹H-NMR spectroscopy,one single diastereomer was obtained.

MS: 387.1 (M+Na)⁺, 382.2 (M+NH₄)⁺, 328.2, 319.2, 279.2, 203.2.

c] (2S)-3-(4-Benzyloxy-2-chloro-phenyl)-2-ethoxy-propionic acid methylester

In analogy to the procedure described in example 1 c],(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester was treated with triethylsilane in trifluoroaceticacid to yield (2S)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 371.4 (M+Na)⁺, 366.2 (M+NH₄)⁺, 303.2, 269.2, 222.2, 187.2.

d] (2S)-3-(2-Chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methylester

Dimethyl sulfide (5.8 ml, 79 mmol) and boron trifluoride diethyletherate (46% purity, 4.3 ml, 16 mmol) were added to a ice cold solutionof (2S)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-propionic acid methylester (1.1 g, 3.2 mmol) in dichloromethane (34 ml) under an argonatmosphere. The mixture was stirred for 5 h at ambient temperature,poured into ice water/brine 1/1 and extracted two times withdichloromethane. The combined extracts were washed with ice water/brine1/1 and dried over sodium sulfate. Removal of the solvent under reducedpressure gave a colorless oil which was purified by columnchromatography (silica gel, cyclohexane/AcOEt) to yield 0.6 g (2.3 mmol,74%) of the title compound as colorless oil.

MS: 281.0 (M+Na)⁺, 276.1 (M+NH₄)⁺, 251.3, 213.3, 187.2.

e](S)-3-[2-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl esterwas reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in thepresence of cesium carbonate and potassium iodide to yield(S)-3-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 452.3 (M+Na)⁺, 430.3 (M+H)⁺, 251.3, 213.3, 172.2.

f](S)-3-[2-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid as colorless solid.

MS: 438.0 (M+Na)⁺, 416.1 (M+H)⁺, 371.4, 304.1, 263.1, 213.3, 172.3.

Example 16 a](S)-3-{2-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester(example 15 d]) was reacted with4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (example 5b]) in the presence of cesium carbonate and potassium iodide to yield(S)-3-{2-chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 484.2 (M+Na)⁺, 462.2 (M+H)⁺, 345.1, 245.3, 204.2, 166.4.

b](S)-3-{2-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{2-chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{2-chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid as colorless solid.

MS: 470.0 (M+Na)⁺, 448.2 (M+H)⁺, 371.4, 275.2, 245.3, 204.2, 187.3.

Example 17 a](S)-3-{2-Chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester(example 15 d]) was reacted with4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-3-{2-chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 510.3 (M+Na)⁺, 488.3 (M+H)⁺, 271.3, 230.2, 188.3.

b](S)-3-{2-Chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{2-chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{2-chloro-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid as colorless foam.

MS: 496.1 (M+Na)⁺, 474.2 (M+H)⁺, 424.3, 271.2, 230.2, 188.3, 172.2.

Example 18 a](S)-3-{2-Chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester(example 15 d]) was reacted with4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-3-{2-chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 470.1 (M+Na)⁺, 448.2 (M+H)⁺, 269.1, 231.2, 190.3, 163.3.

b](S)-3-{2-Chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{2-chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{2-chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid as colorless solid.

MS: 456.1 (M+Na)⁺, 434.2 (M+H)⁺, 428.3, 382.1, 279.1, 231.2, 190.3.

Example 19 a](S)-3-[2-Chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester(example 15 d]) was reacted with4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1 e]) in the presenceof cesium carbonate and potassium iodide to yield(S)-3-[2-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 444.2 (M+H)⁺, 319.3, 279.2, 227.3, 186.3, 181.2, 166.3.

b](S)-3-[2-Chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-[2-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-[2-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid as colorless liquid.

MS: 430.3 (M+H)⁺, 390.2, 349.3, 292.4, 279.2, 186.3, 176.2, 161.3.

Example 20 a](S)-3-{2-Chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester(example 15 d]) was reacted with4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole (prepared from2-methoxy-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-3-{2-chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 482.2 (M+Na)⁺, 360.2 (M+H)⁺, 391.2, 330.3, 284.1, 254.2, 202.2.

b](S)-3-{2-Chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{2-chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{2-chloro-4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid as colorless foam.

MS: 468.1 (M+Na)⁺, 446.2 (M+H)⁺, 371.4, 329.2, 269.2, 202.1.

Example 21 a] 1-Bromo-2-trifluoromethyl-4-(phenylmethoxy)-benzene

A solution of 1-trifluoromethyl-3-(phenylmethoxy)-benzene (5.7 g, 22.6mmol) in glacial acetic acid (25 ml) with sodium acetate (2.7 g, 32.5mmol) was cooled to 0° C. and bromine (1.6 ml, 31.7 mmol) was addedslowly with stirring. A calcium chloride guard tube was fitted and themixture was stirred in the dark, at room temperature, for 24 h. Theresulting slurry was diluted with dichloromethane and washed with 10%aqueous sodium thiosulphate, aqueous potassium carbonate, and water. Theorganic layer was dried over sodium sulfate and the solvent was removedunder reduced pressure to give a yellow oil, which was purified bycolumn chromatography (silica gel, cyclohexane) to yield 6 g of acolorless oil. According to ¹H-NMR the oil consists of a 1/1 mixture ofstarting material and the title compound. This mixture was used in thenext step without further purification.

b] 4-Benzyloxy-2-trifluoromethyl-benzaldehyde

In analogy to the procedure described in example 8 c],1-bromo-2-trifluoromethyl-4-(phenylmethoxy)-benzene was treated withn-BuLi and N,N-dimethylformamide in dry tetrahydrofuran to yield4-benzyloxy-2-trifluoromethyl-benzaldehyde as colorless liquid.

MS: 298.3 (M+NH₄)⁺, 281.1 (M)⁺, 236.1, 224.3, 181.2.

c](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 a],(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C.Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M.Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10,1353-1367) was reacted with 4-benzyloxy-2-trifluoromethyl-benzaldehydein the presence of triethylamine and di-n-butylboron triflate to give(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-oneas colorless liquid. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 566.3 (M+Na)⁺, 561.4 (M+NH₄)⁺, 526.3, 458.2, 349.3, 301.3.

d](2S,3R)-3-(4-Benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

In analogy to the procedure described in example 1 b],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-onewas treated with sodium methoxide in methanol to give(2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester as colorless liquid. According to ¹H-NMR spectroscopy,one single diastereomer was obtained.

MS: 421.2 (M+Na)⁺, 416.2 (M+NH₄)⁺, 381.3, 353.2, 313.3, 222.2, 192.4.

e] (2S)-3-(4-Benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-propionic acidmethyl ester

In analogy to the procedure described in example 1 c],(2S,3R)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester was treated with triethylsilane in trifluoroaceticacid to yield(2S)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-propionic acidmethyl ester as colorless liquid.

MS: 405.4 (M+Na)⁺, 400.4 (M+NH₄)⁺, 337.2, 269.2.

f] (2S)-2-Ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acidmethyl ester

In analogy to the procedure described in example 1 d],(2S)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-propionic acidmethyl ester was hydrogenated over 10% palladium on charcoal to give(2S)-2-ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acidmethyl ester as yellow solid.

MS: 291.1 (M−H)⁻, 255.2, 206.0, 174.1, 141.1.

g](S)-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acidmethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazolein the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 486.3 (M+Na)⁺, 464.3 (M+H)⁺, 411.0, 371.4, 304.2, 279.3.

h](S)-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionicacid as colorless solid.

MS: 448.2 (M−H)⁻, 431.1, 402.2, 277.2, 231.1.

Example 22 a](S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acidmethyl ester (example 21 f]) was reacted with with4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionicacid methyl ester as colorless solid.

MS: 504.3 (M+Na)⁺, 482.3 (M+H)⁺, 428.5, 345.2, 303.8, 269.2, 231.2.

b](S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionicacid as colorless liquid.

MS: 466.3 (M−H)⁻, 420.1, 376.3, 316.9, 277.1, 231.2.

Example 23 a]2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde

A solution of 2,4-dihydroxy-benzaldehyde (2 g, 14.5 mmol) in 20 ml THFwas cooled to 0° C. To this solution were added triphenylphosphine (9.7g, 37 mmol), 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethanol (2.84 g, 14 mmol)and finally during 0.75 hours a solution of di-tert-butylazodicarboxylate (8.52 g, 37 mmol) in 20 ml THF. The reaction mixturewas stirred overnight at room temperature, evaporated to dryness,purified by chromatography (SiO₂; AcOEt/heptane) and the product wascrystallized from AcOEt/ether/heptane to yield 2.2 g (46%) of the titlecompound as a colorless solid.

b]2-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde

To a solution of2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (540mg, 1.67 mmol) in 8 ml N,N-dimethylformamide cooled to 0° C., were added398 mg (5.85 mol) imidazole and 1.1 ml (5.85 mmol)thexyl-dimethylchlorosilane. The reaction mixture was stirred 50 minutesat 0° C., diluted with AcOEt, washed with water/ice, HCl (1M)/ice andbrine and the aqueous layer was extracted with AcOEt. The combinedorganic layers were dried over Na₂SO₄ and evaporated. Chromatography(SiO₂; AcOEt/heptane) delivered 346 mg (45%) of the title compound as anoil.

MS: (M+H⁺)⁺466.3.

c](S)-4-Benzyl-3-((2S,3R)-3-{2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-2-methoxy-propionyl)-oxazolidin-2-one

1.8 g (7.21 mmol) (S)-4-Benzyl-3-methoxyacetyl-oxazolidin-2-one (for thepreparation of (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one see: D.Hunziker, N. Wu, K. Kenoshita, D. E. Cane, C. Khosla, Tetrahedron Lett.1999, 40, 635-638) were dissolved under an argon atmosphere in 10 mlCH₂Cl₂ and treated with 1.44 ml (8.42 mmol) Hünig's base. After coolingto −78° C., nBu₂BOTf was added slowly (7.21 ml of 1M solution in CH₂Cl₂)and enolborinate formation allowed to proceed for 0.25 hours at −78° C.and for 1 hour at 0° C. After recooling to −78° C., a solution of 2.8 g(6 mmol) of2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehydein 10 ml CH₂Cl₂ was added via dropping funnel during 90 minutes and themixture kept for 95 minutes at −78° C. and for one hour at 0° C. Pouringonto crashed ice, twofold extraction with AcOEt, washing with brine andwater, drying over magnesium sulfate, and evaporation of the solvents,followed by chromatography (silica gel, heptane/AcOEt) left finally2.905 g (67%) of the title compound as a yellow oil. According to ¹H-NMRspectroscopy, one of the four isomers is strongly predominating. Theconfiguration was tentatively assigned as 2S,3R according to D. Haigh etal., Tetrahedron: Asymmetry 1999, 10, 1353-1367.

MS: (M+Na⁺)+ 737.3, (M+H⁺)+ 715.3.

d](S)-4-Benzyl-3-(3-{2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2S)-methoxy-propionyl)-oxazolidin-2-one

The above prepared(S)-4-benzyl-3-((2S,3R)-3-{2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-2-methoxy-propionyl)-oxazolidin-2-one(2.8 g, 3.91 mmol) was dissolved in 10 ml of trifluoroacetic acid,treated at 0° C. with 10 ml of triethylsilane and then kept for 3 hoursat ambient temperature. The reaction mixture was then poured ontocrashed ice/AcOEt/NaOH (1M), the organic layer was washed with water andbrine, dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂, heptane/AcOEt) delivered 1.6 g (58%) of the titlecompound (purity ˜80%) as a yellow foam.

MS: 596.4 (M)⁺.

e](S)-4-Benzyl-3-(3-[2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-(2S)-2-methoxy-propionyl)-oxazolidin-2-one

To a solution of(S)-4-benzyl-3-(3-{2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(2S)-methoxy-propionyl)-oxazolidin-2-one(1.6 g, 2.29 mmol) in 10 ml methanol, was added NH₄F (169 mg, 4.58 mmol)and the reaction mixture kept at r.t. for 2 hours. It was then dilutedwith AcOEt, washed with water/ice and brine, the aqueous layer wasextracted with AcOEt, the combined organic layers dried over Na₂SO₄ andevaporated. The crude product (1.22 g) was found to be a mixture of thetitle compound and of(S)-3-{2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionicacid methyl ester and used without purification for the last step.

f](S)-3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionicacid

1.22 g of the mixture prepared above was dissolved in 5 ml of THF andtreated with 5 ml of 1N NaOH. The reaction mixture was kept at 0° C.overnight. Then, it was washed twice with ether. The aqueous layer wasacidified (pH 3 with HCl (1M)/ice), extracted twice with AcOEt, theorganic layers were dried over magnesium sulfate, and evaporated to givea crude product, which was purified by crystalization from AcOEt/heptaneto remove the chiral auxiliary. Thereby, 0.240 g (27%) of the titlecompound was obtained as a white solid. According to chiral HPLC(Chiralpak-AD), an enantiomeric excess of close to 100% was observed.

MS: 396.2 (M−H)⁻.

Example 24 a](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 a],(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C.Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M.Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10,1353-1367) was reacted with 4-benzyloxy-2-methoxy-benzaldehyde in thepresence of triethylamine and di-n-butylboron triflate to give(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-oneas light yellow solid. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 528.3 (M+Na)⁺, 523.3 (M+NH₄)⁺, 488.3, 442.4, 311.2, 239.3.

b] (2S,3R)-3-(4-Benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

In analogy to the procedure described in example 1 b],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-onewas treated with sodium methoxide in methanol to give(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester as colorless liquid. According to ¹H-NMR spectroscopy,one single diastereomer was obtained.

MS: 383.2 (M+Na)⁺, 378.2 (M+NH₄)⁺, 343.2, 311.2, 283.2, 239.3, 163.2.

c] (2S)-2-Ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methylester

A solution of(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester (100 mg, 200 μmol) and oxalic acid dihydrate (150 mg,1.2 mmol) in isopropanol (2 ml) was hydrogenated at a pressure of 50atmospheres over 10% palladium on charcoal (20 mg) at ambienttemperature for 6.5 h. The catalyst was filtered off and the solventevaporated under reduced pressure. The residue was dissolved in icewater/aqueous sodium bicarbonate solution 1/1 and extracted two timeswith ethyl acetate. The combined extracts were washed two times with icewater/brine 1/1 and dried over sodium sulfate. The solvent was removedunder reduced pressure to give a yellow liquid which was purified bycolumn chromatography (silica gel, cyclohexane/AcOEt) to yield 43 mg(170 μmol, 85%) of the title compound as light yellow liquid.

MS: 277.1 (M+Na)⁺, 209.2, 195.3, 181.2, 177.2, 167.2.

d](S)-2-Ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl esterwas reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in thepresence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 448.2 (M+Na)⁺, 426.3 (M+H)⁺, 380.2, 319.2, 213.3, 172.2.

e](S)-2-Ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless solid.

MS: 410.6 (M−H)⁻, 369.9, 304.2, 285.2, 261.3, 238.9, 229.6, 191.3.

Example 25 a](S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester(example 24 c]) was reacted with4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatmentwith POCl₃ in analogy to the procedures described in examples 5 a] and 2b]) in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester as orange liquid.

MS: 490.2 (M+Na)⁺, 468.2 (M+H)⁺, 344.3, 311.2, 255.2, 214.4, 198.4.

b](S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid as colorless solid.

MS: 476.2 (M+Na)⁺, 454.3 (M+H)⁺, 404.5, 255.2, 214.3.

Example 26 a](S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester(example 24 c]) was reacted with4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (examples 5b]) in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 480.4 (M+Na)⁺, 458.3 (M+H)⁺, 412.2, 245.3, 204.2, 177.2.

b](S)-2-Ethoxy-3-[4-{2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid as colorless solid.

MS: 466.1 (M+Na)⁺, 444.2 (M+H)⁺, 392.1, 365.2, 297.3, 245.3, 204.2.

Example 27 a](S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester(example 24 c]) was reacted with4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (examples 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 506.5 (M+Na)⁺, 484.3 (M+H)⁺, 323.3, 271.3, 230.2, 188.3.

b](S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid as colorless solid.

MS: 492.2 (M+Na)⁺, 470.2 (M+H)⁺, 357.2, 335.2, 279.2, 235.2, 187.3.

Example 28 a](S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester(example 24 c]) was reacted with4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 482.2 (M+Na)⁺, 460.2 (M+H)⁺, 414.1, 357.2, 335.3, 279.2, 235.2,206.1.

b](S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionicacid as colorless liquid.

MS: 468.1 (M+Na)⁺, 446.1 (M+H)⁺, 394.2, 352.2, 302.2, 269.2, 206.1,149.1.

Example 29 a] 4-Benzyloxy-2,6-dimethyl-benzaldehyde

In analogy to the procedure described in example 8 a],4-hydroxy-2,6-dimethyl-benzaldehyde was reacted with benzyl bromide inthe presence of potassium carbonate to yield4-benzyloxy-2,6-dimethyl-benzaldehyde as orange liquid.

MS: 241.2 (M+H)⁺, 181.0.

b](S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one

In analogy to the procedure described in example 1 a],(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of(S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C.Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M.Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10,1353-1367) was reacted with 4-benzyloxy-2,6-dimethyl-benzaldehyde in thepresence of triethylamine and di-n-butylboron triflate to give(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-oneas colorless liquid. According to ¹H-NMR spectroscopy, one of the fourisomers is strongly predominating. The configuration was tentativelyassigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry1999, 10, 1353-1367.

MS: 526.3 (M+Na)⁺, 486.3, 425.3, 358.2, 309.1, 281.2, 253.1, 237.2,178.2.

c](2S,3R)-3-(4-Benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester

In analogy to the procedure described in example 1 b],(S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-onewas treated with sodium methoxide in methanol to give(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester as colorless liquid. According to ¹H-NMR spectroscopy,one single diastereomer was obtained.

MS: 381.2 (M+Na)⁺, 376.3 (M+NH₄)⁺, 341.2, 313.2, 269.2, 213.3, 187.2.

d] (2S)-3-(4-Benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acidmethyl ester

In analogy to the procedure described in example 1 c],(2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionicacid methyl ester was treated with triethylsilane in trifluoroaceticacid to yield(2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acid methylester as colorless liquid.

MS: 360.3 (M+NH₄)⁺, 284.1, 269.2, 201.1, 163.3.

e] (2S)-2-Ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester

In analogy to the procedure described in example 1 d],(2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acid methylester was hydrogenated over 10% palladium on charcoal to give(2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester as colorless liquid.

MS: 275.2 (M+Na)⁺, 270.3 (M+NH₄)⁺, 253.3 (M+H)⁺, 207.2, 165.3.

f](S)-3-[2,6-Dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in thepresence of cesium carbonate and potassium iodide to yield(S)-3-[2,6-dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 446.4 (M+Na)⁺, 357.0, 275.0, 169.1.

g](S)-3-[2,6-Dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-[2,6-dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-[2,6-dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid as colorless solid.

MS: 432.2 (M+Na)⁺, 410.2 (M+H)⁺, 355.0, 329.4, 293.4, 244.3, 174.3,166.3.

Example 30 a](S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester (example 29 e]) was reacted with4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 504.3 (M+Na)⁺, 482.3 (M+H)⁺, 299.3, 271.2, 230.2, 188.3, 161.3.

b](S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid as colorless foam.

MS: 490.2 (M+Na)⁺, 468.2 (M+H)⁺, 416.2, 305.2, 271.3, 230.2, 188.3.

Example 31 a](S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester (example 29 e]) was reacted with4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatmentwith POCl₃ in analogy to the procedures described in examples 5 a] and 2b]) in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 488.3 (M+Na)⁺, 466.3 (M+H)⁺, 255.2, 214.4, 187.3.

b](S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid as colorless solid.

MS: 474.2 (M+Na)⁺, 452.3 (M+H)⁺, 400.4, 357.1, 279.2, 214.4.

Example 32 a](S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester (example 29 e]) was reacted with4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in the presence of cesium carbonate and potassium iodide to yield(S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionicacid methyl ester as colorless liquid.

MS: 480.3 (M+Na)⁺, 458.3 (M+H)⁺, 412.2, 330.2, 302.2, 247.2, 206.1.

b](S)-3-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],(S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionicacid methyl ester was treated with LiOH to obtain(S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionicacid as colorless solid.

MS: 466.2 (M+Na)⁺, 444.2 (M+H)⁺, 380.2, 305.2, 287.2, 254.3, 215.3,206.2, 198.2.

Example 33 a](S)-2-Ethoxy-3-[4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methylester (example 29 e]) was reacted with4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole (example 5b]) in the presence of cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester as colorless liquid.

MS: 478.3 (M+Na)⁺, 456.3 (M+H)⁺, 371.4, 339.1, 304.1, 245.3, 222.2,204.2.

b](S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid as colorless solid.

MS: 464.2 (M+Na)⁺, 442.3 (M+H)⁺, 349.3, 285.1, 266.2, 245.4, 225.3,187.2.

Example 34 a] 3-(4-Benzyloxy-2-methyl-phenyl)-2(Z,E)-ethoxy-acrylic acidethyl ester

A suspension of (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride[Tetrahedron 50(25), 7543-56(1994)] (35.5 g, 82.9 mmol) and DBU (13.6ml, 91.2 mmol) in THF (60 ml) was stirred for 10 min at ambienttemperature. 4-Benzyloxy-2-methyl-benzaldehyde (12.5 g, 55.2 mmol) wasadded and the reaction mixture was heated under reflux for 16 h. Thesolvent was concentrated at reduced pressure, the residue was taken upin AcOEt and washed with saturated aqueous NH₄Cl solution and brine. Theorganic layer was dried over sodium sulfate, the solvent removed underreduced pressure and the residue purified by column chromatography(silica gel, hexane/AcOEt) to give 14.5 g (42.6 mmol, 77%) of the titlecompound as yellow liquid.

MS: 340.2 (M)⁺, 249.2, 147.1, 91.1.

b] [rac]-2-Ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethylester

A solution of 3-(4-benzyloxy-2-methyl-phenyl)-2(Z,E)-ethoxy-acrylic acidethyl ester (1 g, 2.9 mmol) in ethanol (50 ml) was hydrogenated over 10%palladium on charcoal (250 mg) at ambient temperature for 2 h. Thecatalyst was filtered off and the solvent evaporated under reducedpressure to give 600 mg (2.4 mmol, 81%) of the title compound as yellowliquid which was used in the next step without further purification.

MS: 270.4 (M+NH₄)⁺, 253 (M)⁺, 207.2, 165.3.

c][rac]-3-{4-[2-(3,5-Dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl esterwas reacted with 4-chloromethyl-2-(3,5-dichloro-phenyl)-5-methyl-oxazole(prepared from 3,5-dichloro-benzaldehyde and diacetyl monoxyme followedby treatment with POCl₃ in analogy to the procedures described inexamples 2 a] and b]) in the presence of cesium carbonate and potassiumiodide to yield[rac]-3-{4-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester as colorless liquid.

MS: 493.3 (M+H)⁺, 453.3, 375.4, 331.4, 275.2, 240.2, 200.2.

d](S)-3-[4-[2-(3,5-Dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl]-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],[rac]-3-{4-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester was treated with LiOH to obtain[rac]-3-{4-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 486.1 (M+Na)⁺, 466.1 (M+H)⁺, 464.2 (M+H)⁺, 433.1, 351.0, 293.2,269.2, 187.2.

Example 35 a][rac]-3-{4-[2-(3,5-Dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-2-(3,5-dimethyl-phenyl)-5-methyl-oxazole (prepared from3,5-dimethyl-benzaldehyde and diacetyl monoxyme followed by treatmentwith POCl₃ in analogy to the procedures described in examples 2 a] andb]) in the presence of cesium carbonate and potassium iodide to yield[rac]-3-{4-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester as colorless liquid.

MS: 474.2 (M+Na)⁺, 452.3 (M+H)⁺, 431.4, 375.3, 331.3, 275.2, 241.3,200.2.

b](S)-3-{4-[2-(3,5-Dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],[rac]-3-{4-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester was treated with LiOH to obtain[rac]-3-{4-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 422.3 (M−H)⁻, 375.9, 339.2, 319.3, 305.6, 282.2, 255.4, 222.9.

Example 36 a][rac]-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-5-methyl-2-(2-trifluoromethyl-phenyl)-oxazole (preparedfrom 2-trifluoromethyl-benzaldehyde and diacetyl monoxyme followed bytreatment with POCl₃ in analogy to the procedures described in examples5 a] and 2 b]) in the presence of cesium carbonate and potassium iodideto yield[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester as colorless liquid.

MS: 514.2 (M+Na)⁺, 492.2 (M+H)⁺, 448.2, 407.2, 322.2, 281.1, 266.3,240.2.

b](S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 462.2 (M−H)⁻, 416.4, 372.1, 353.4, 337.3, 309.5, 255.0, 223.0.

Example 37 a][rac]-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole (preparedfrom 3-trifluoromethyl-benzaldehyde and diacetyl monoxyme followed bytreatment with POCl₃ in analogy to the procedures described in examples5 a] and 2 b]) in the presence of cesium carbonate and potassium iodideto yield[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester as colorless liquid.

MS: 514.3 (M+Na)⁺, 509.4 (M+NH₄)⁺, 492.2 (M+H)⁺, 446.1, 281.1, 240.2.

b](S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless solid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 462.1 (M−H)⁻, 404.8, 387.0, 353.2, 319.0, 282.9, 268.7, 255.2,241.0, 226.9.

Example 38 a][rac]-2-Ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-2-(4-fluoro-phenyl)-5-methyl-oxazole (prepared from4-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 2 a] and b]) inthe presence of cesium carbonate and potassium iodide to yield[rac]-2-ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester as colorless liquid.

MS: 442.2 (M+H)⁺, 391.2, 319.3, 231.2, 198.2, 190.3, 181.2, 166.3.

b](S)-2-Ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 412.2 (M−H)⁻, 366.0, 322.3, 303.1, 283.3, 254.8, 222.9, 194.6.

Example 39 a][rac]-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (preparedfrom 4-trifluoromethyl-benzaldehyde and diacetyl monoxyme followed bytreatment with POCl₃ in analogy to the procedures described in examples2 a] and b]) in the presence of cesium carbonate and potassium iodide toyield[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester as colorless liquid.

MS: 514.2 (M+Na)⁺, 509.4 (M+NH₄)⁺, 492.2 (M+H)⁺, 446.2, 418.2, 281.1,240.2, 172.2

b](S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless solid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 462.2 (M−H)⁻, 416.2, 399.1, 372.3, 341.7, 317.1, 255.4.

Example 40 a][rac]-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatmentwith POCl₃ in analogy to the procedures described in examples 5 a] and 2b]) in the presence of cesium carbonate and potassium iodide to yield[rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester as colorless liquid.

MS: 488.3 (M+Na)⁺, 466.2 (M+H)⁺, 422.3, 391.2, 279.2, 214.4.

b](S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 436.2 (M−H)⁻, 410.9, 389.8, 363.3, 328.7, 305.0, 282.9, 254.9,222.8.

Example 41 a][rac]-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazole (preparedfrom 3,4,5-trimethoxy-benzaldehyde and diacetyl monoxyme followed bytreatment with POCl₃ in analogy to the procedures described in examples2 a] and b]) in the presence of cesium carbonate and potassium iodide toyield[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester as yellow liquid.

MS: 536.3 (M+Na)⁺, 514.3 (M+H)⁺, 470.2, 340.0, 303.2, 262.2, 214.3,168.2.

b](S)-2-Ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless solid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 485.3 (M)⁻.

Example 42 a][rac]-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid ethyl ester

In analogy to the procedure described in example 7 c],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (preparedfrom 4-fluoro-2-hydroxy-benzaldehyde [J. Chem. Soc., Perkin Trans. 1(1994), (13), 1823-31] by i) treatment with ethyl iodide, potassiumcarbonate in N,N-dimethylformamide to give2-ethoxy-4-fluoro-benzaldehyde; ii) conversion of2-ethoxy-4-fluoro-benzaldehyde into4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole in analogyto the procedures described in examples 2 a] and b]; iii) conversion of4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole into2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol bytreatment with sodium cyanide in DMSO followed by hydrolysis of thenitrile function with sodium hydroxide in ethanol/water at reflux andreduction of the acid formed with BH₃xTHF in tetrahydrofuran at roomtemperature) in the presence of triphenylphosphine and diethylazodicarboxylate to yield[rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid ethyl ester as light yellow liquid.

MS: 522.2 (M+Na)⁺, 500.3 (M+H)⁺, 456.3, 426.3, 398.2, 248.2, 220.2,149.1.

b](S)-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid as colorless solid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 470.1 (M−H)⁻, 424.2, 387.0, 326.5, 281.1, 255.0, 204.9.

Example 43 a][rac]-2-Ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 7 c],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with3-(5-methyl-2-phenyl-oxazol-4-yl)-propan-1-ol (J. L. Collins, M. Dezube,J. A. Oplinger, A. Jeffrey, T. M. Willson, International Patent Appl.,Publication No. WO0008002(A1), 2000) in the presence oftriphenylphosphine and diethyl azodicarboxylate to yield[rac]-2-ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid ethyl ester as yellow liquid.

MS: 474.3 (M+Na)⁺, 452.5 (M+H)⁺, 382.4, 241.3.

b](S)-2-Ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 422.3 (M−H)⁻, 376.3, 299.1.

Example 44 a](S)-2-Ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 1 d]) was reacted with 4-chloromethyl-2-phenyl-oxazole[prepared from benzamide and 1,3-dichloroacetone as described in Bioorg.Med. Chem. Lett. (2000), 10(17), 2041-2044] in the presence of cesiumcarbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless liquid.

MS: 418.2 (M+Na)⁺, 396.2 (M+H)⁺, 350.2, 336.3, 308.1, 251.2, 186.3,158.2.

b](S)-2-Ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-methyl-4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless solid.

MS: 404.3 (M+Na)⁺, 382.2 (M+H)⁺, 325.2, 293.2, 250.2, 212.3, 172.3,158.2.

Example 45 a][rac]-3-{4-[2-(2-Chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-2-(2-chloro-phenyl)-oxazole [prepared from2-chloro-benzamide and 1,3-dichloroacetone in analogy to the proceduredescribed for the synthesis of 4-chloromethyl-2-phenyl-oxazole inBioorg. Med. Chem. Lett. (2000), 10(17), 2041-2044] in the presence ofcesium carbonate and potassium iodide to yield[rac]-3-{4-[2-(2-chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid-ethyl ester as colorless liquid.

MS: 466.1 (M+Na)⁺, 444.2 (M+H)⁺, 371.4, 327.0, 192.2, 163.4.

b](S)-3-{4-[2-(2-Chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 g],[rac]-3-{4-[2-(2-chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid ethyl ester was treated with LiOH to obtain[rac]-3-{4-[2-(2-chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 438.2 (M+Na)⁺, 416.1 (M+H)⁺, 340.4, 280.2, 220.4, 192.2, 173.1.

Example 46 a][rac]-2-Ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester(example 34 b]) was reacted with4-chloromethyl-2-(3-methoxy-phenyl)-oxazole [prepared from3-methoxy-benzamide and 1,3-dichloroacetone in analogy to the proceduredescribed for the synthesis of 4-chloromethyl-2-phenyl-oxazole inBioorg. Med. Chem. Lett. (2000), 10(17), 2041-2044] in the presence ofcesium carbonate and potassium iodide to yield[rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester as colorless liquid.

MS: 462.2 (M+Na)⁺, 440.2 (M+H)⁺, 394.2, 366.2, 291.4.

b](S)-2-Ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid

In analogy to the procedure described in example 1 g],[rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid ethyl ester was treated with LiOH to obtain[rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid as colorless liquid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 434.3 (M+Na)⁺, 412.2 (M+H)⁺, 360.1, 304.1, 261.2, 229.2, 188.3,160.3.

Example 47 a][rac]-3-(4-Benzyloxy-2-ethoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acidethyl ester [mixture of diastereomers]

LDA was prepared by adding 13.3 ml n-BuLi (1.5 M, hexane) to a solutionof 2.85 ml (20.0 mmol) of diisopropylamine in 90 ml of abs. THF at −5°C. After cooling to −78° C., 2.81 ml (20.0 mmol) of ethyl ethoxyacetate,dissolved in 10 ml of abs. THF, was added and the mixture kept for 15minutes at that temperature to ensure complete deprotonation. 2.05 g(8.0 mmol) of 4-benzyloxy-2-ethoxy-benzaldehyde [prepared from2-hydroxy-4-benzyloxy-benzaldehyde and ethyl iodide in analogy to theprocedure described for 4-benzyloxy-2-isopropoxy-benzaldehyde inChemical & Pharmaceutical Bulletin (1998), 46(2), 222-230:2-hydroxy-4-benzyloxy-benzaldehyde, isopropyl bromide, potassium iodide,potassium carbonate, N,N-dimethylformamide, 100° C.], dissolved in 20 mlof abs. THF, was then added. After stirring for 30 minutes at dry icetemperature, the reaction mixture was quenched with ammonium chloridesolution, warmed up to 0° C., then extracted twice with AcOEt, washedwith water, dried over sodium sulfate, and evaporated to dryness. Flashchromatography (SiO₂, hexane/AcOEt=9:1 to 1:1) yielded 3.09 g (99% oftheory) of[rac]-3-(4-benzyloxy-2-ethoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acidethyl ester [mixture of diastereomers] as light yellow oil.

MS: 371.4 [(M+H)⁺−H₂O].

b] 3-(4-Benzyloxy-2-ethoxy-phenyl)-2(Z,E)-ethoxy-acrylic acid ethylester

3.26 g (8.39 mmol) of[rac]-3-(4-benzyloxy-2-ethoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acidethyl ester [mixture of diastereomers] and 0.15 g (0.84 mmol) 4-toluenesulfonic acid were stirred in 200 ml benzene at reflux for 30 minutes.Evaporation to dryness followed by flash chromatography (SiO₂,hexane/AcOEt=95:5 to 4:1) yielded 2.12 g (68% of theory) of3-(4-benzyloxy-2-ethoxy-phenyl)-2(Z,E)-ethoxy-acrylic acid ethyl esteras light yellow oil.

MS: 370.1 (M)⁺.

c] [rac]-2-Ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethylester

0.90 g of Pd/C (10%) were added under argon to 4.49 g (12.1 mmol) of3-(4-benzyloxy-2-ethoxy-phenyl)-2(Z,E)-ethoxy-acrylic acid ethyl esterdissolved in 80 ml of ethanol. The atmosphere was then replaced with H₂,and the suspension was rapidly stirred at room temperature for twohours. Filtration over dicalite and evaporation of the solvents left4.23 g of a light brown oil. Flash chromatography (SiO₂,hexane/AcOEt=95:5 to 1:1) yielded 3.41 g (99% of theory) of[rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl esteras light yellow oil.

MS: 281.0 (M−H)⁻.

d](S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl esterwas reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole(prepared from 4-tert-butyl-benzaldehyde and diacetyl monoxyme followedby treatment with POCl₃ in analogy to the procedures described inexamples 5 a] and 2 b]) in N,N-dimethylformamide in the presence ofpotassium carbonate to yield[rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionicacid ethyl ester, which was further saponified in analogy to theprocedure described in example 1 g], to yield[rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionicacid as colorless amorphous solid, which can be separated into itsantipodes by methods known in the art, such as separation of theantipodes via diastereomeric salts by crystallization with opticallypure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 480.4 (M−H)⁻.

Example 48(S)-2-Ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester(example 47 c]) was reacted with4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b])in N,N-dimethylformamide in the presence of potassium carbonate to yield[rac]-2-ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid ethyl ester, which was further saponified in analogy to theprocedure described in example 1 g], to yield[rac]-2-ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid as colorless solid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 482.3 (M−H)⁻.

Example 49(S)-3-[4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl]-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester(example 47 c]) was reacted with4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment withPOCl₃ in analogy to the procedures described in examples 5 a] and 2 b])in N,N-dimethylformamide in the presence of potassium carbonate to yield[rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionicacid ethyl ester, which was further saponified in analogy to theprocedure described in example 1 g], to yield[rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionicacid as colorless solid, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 458.2 (M−H)⁻.

Example 50(S)-2-Ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 7 c],[rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester(example 47 c]) was reacted with2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol in tetrahydrofuran in thepresence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate)to yield[rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester, which was further saponified in analogy to theprocedure described in example 1 g], to yield[rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionicacid as colorless oil, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 438.2 (M−H)⁻.

Example 51(S)-2-Ethoxy-3-{2-ethoxy-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid

In analogy to the procedure described in example 7 c],[rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester(example 47 c]) was reacted with3-(5-methyl-2-phenyl-oxazol-4-yl)-propan-1-ol (J. L. Collins, M. Dezube,J. A. Oplinger, A. Jeffrey, T. M. Willson, International Patent Appl.,Publication No. WO0008002(A1), 2000) in tetrahydrofuran in the presenceof triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield[rac]-2-ethoxy-3-{2-ethoxy-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid ethyl ester, which was further saponified in analogy to theprocedure described in example 1 g], to yield[rac]-2-ethoxy-3-{2-ethoxy-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid as colorless oil, which can be separated into its antipodes bymethods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 452.2 (M−H)⁻.

Example 52 a][rac]-3-(4-Benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid ethyl ester [mixture of diastereomers]

In analogy to the procedure described in example 47 a],4-benzyloxy-2-isopropoxy-benzaldehyde [Chemical & PharmaceuticalBulletin (1998), 46(2), 222-230] was reacted with the enolate of ethylethoxyacetate, to yield[rac]-3-(4-benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid ethyl ester as a mixture of diastereomers in form of a light yellowoil.

MS: 402.0 (M)⁺.

b] [rac]-2-Ethoxy-3-(4-hydroxy-2-isopropoxy-phenyl)-propionic acid ethylester

0.80 g of Pd/C (10%) and 6.0 g of oxalic acid dihydrate were added underargon to 3.20 g (7.95 mmol) of[rac]-3-(4-benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionicacid ethyl ester [mixture of diastereomers] dissolved in 60 ml ofisopropanol. This solution was stirred for 24 hours at room temperatureand 50 bar H₂. Filtration over dicalite and evaporation of the solvents,followed by flash chromatography (SiO₂, hexane/AcOEt=9:1 to 1:1) left0.69 g (29% of theory) of[rac]-2-ethoxy-3-(4-hydroxy-2-isopropoxy-phenyl)-propionic acid ethylester as yellow oil.

MS: 295.2 (M−H)⁻.

c](S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionicacid

In analogy to the procedure described in example 1 f],[rac]-2-ethoxy-3-(4-hydroxy-2-isopropoxy-phenyl)-propionic acid ethylester was reacted with2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (prepared from4-tert-butyl-benzaldehyde and diacetyl monoxyme followed by treatmentwith POCl₃ in analogy to the procedures described in examples 5 a] and 2b]) in N,N-dimethylformamide in the presence of potassium carbonate toyield[rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionicacid ethyl ester, which was further saponified in analogy to theprocedure described in example 1 g], to yield[rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionicacid as colorless viscous oil, which can be separated into its antipodesby methods known in the art, such as separation of the antipodes viadiastereomeric salts by crystallization with optically pure amines suchas e.g. (R) or (S)-1-phenyl-ethylamine, (R) or(S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or byseparation of the antipodes by specific chromatographic methods usingeither a chiral adsorbens or a chiral eluent to give the title compound.

MS: 494.3 (M−H)⁻.

Example 53 a](S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester

In analogy to the procedure described in example 1 f],(2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester(example 13 f]) was reacted with4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1 e]) in the presenceof cesium carbonate and potassium iodide to yield(S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester as colorless oil.

MS: 450.4 (M+Na)⁺, 445.4 (M+NH₄)⁺, 428.5 (M+H)⁺, 391.4, 279.3, 227.4,186.3.

b](S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid

In analogy to the procedure described in example 1 g],(S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid methyl ester was treated with LiOH to obtain(S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid as colorless liquid.

MS: 412.2 (M−H)⁻, 366.2.

Example A

Tablets containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per tablet Compound of formula (I) 10.0-100.0 mg Lactose125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

1. A method for the treatment of a disease selected from the groupconsisting of diabetes, non-insulin dependent diabetes mellitus,elevated blood pressure, increased lipid and cholesterol levels,atherosclerotic diseases and metabolic syndrome comprisingadministering, to a patient in need thereof, a therapeutically effectiveamount of an optically active compound according to formula (I):

wherein: (a) R¹ is aryl; (b) R² is selected from the group consisting oflower-alkyl and fluoro-lower-alkyl; (c) R³ and R⁴ independently fromeach other are selected from the group consisting of hydrogen, hydroxy,halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy,hydroxy-lower-alkoxy, lower-alkoxy-lower-alkoxy, and lower-alkenyl;wherein at least one of R³ and R⁴ is not hydrogen; (d) R⁵ is selectedfrom the group consisting of lower-alkoxy, fluoro-lower-alkoxy,lower-alkenyloxy, fluoro-lower-alkenyloxy, aryloxy, aryl-lower-alkoxy,and aryl-fluoro-lower-alkoxy; (e) R⁶ is selected from the groupconsisting of hydrogen and lower-alkyl; and (f) n is 1; orpharmaceutically acceptable salts and/or pharmaceutically acceptableesters thereof.
 2. The method according to claim 1, wherein the diseaseis non-insulin dependent diabetes mellitus.
 3. The method according toclaim 1, wherein R¹ is phenyl optionally substituted with 1 to 3substituents independently selected from the group consisting oflower-alkyl, lower-alkoxy, halogen, and fluoro-lower-alkyl.
 4. Themethod according to claim 1, wherein R¹ is selected from the groupconsisting of phenyl, 2-methyl-phenyl, 4-isopropoxy-phenyl,4-fluoro-3-methyl-phenyl, 2-fluoro-phenyl, 4-isopropyl-phenyl,2-ethoxy-4-fluoro-phenyl, 3-methoxy-phenyl, and 4-tert-butyl-phenyl. 5.The method according to claim 1, wherein R² is lower-alkyl.
 6. Themethod according to claim 1, wherein R² is methyl.
 7. The methodaccording to claim 6, wherein R¹ is selected from the group consistingof phenyl, 2-methyl-phenyl, 4-isopropoxy-phenyl,4-fluoro-3-methyl-phenyl, 2-fluoro-phenyl, 4-isopropyl-phenyl,2-ethoxy-4-fluoro-phenyl, 3-methoxy-phenyl, or 4-tert-butyl-phenyl. 8.The method according to claim 1, wherein R³ and R⁴ independently fromeach other are selected from the group consisting of hydrogen, hydroxy,halogen, lower-alkyl, fluoro-lower-alkyl, and lower-alkoxy; wherein atleast one of R³ and R⁴ is not hydrogen.
 9. The method according to claim1, wherein R³ is hydrogen or methyl.
 10. The method according to claim1, wherein R⁴ is selected from the group consisting of methyl, ethyl,fluoro, chloro, trifluoromethyl, hydroxy, methoxy, ethoxy, andisopropoxy.
 11. The method according to claim 7, wherein R⁴ is selectedfrom the group consisting of methyl, ethyl, fluoro, chloro,trifluoromethyl, hydroxy, methoxy, ethoxy, and isopropoxy.
 12. Themethod according to claim 11, wherein R¹ is selected from the groupconsisting of phenyl, 2-methyl-phenyl, 4-isopropoxy-phenyl,4-fluoro-3-methyl-phenyl, 2-fluoro-phenyl, 4-isopropyl-phenyl,2-ethoxy-4-fluoro-phenyl, 3-methoxy-phenyl, and 4-tert-butyl-phenyl. 13.The method according to claim 12, wherein R² is methyl.
 14. The methodaccording to claim 1, wherein R⁵ is lower-alkoxy.
 15. The methodaccording to claim 1, wherein R⁵ is methoxy or ethoxy.
 16. The methodaccording to claim 15, wherein R¹ is selected from the group consistingof phenyl, 2-methyl-phenyl, 4-isopropoxy-phenyl,4-fluoro-3-methyl-phenyl, 2-fluoro-phenyl, 4-isopropyl-phenyl,2-ethoxy-4-fluoro-phenyl, 3-methoxy-phenyl, and 4-tert-butyl-phenyl. 17.The method according to claim 16, wherein R² is methyl.
 18. The methodaccording to claim 17, wherein R³ is hydrogen or methyl.
 19. The methodaccording to claim 18, wherein R⁴ is selected from the group consistingof methyl, ethyl, fluoro, chloro, trifluoromethyl, hydroxy, methoxy,ethoxy, and isopropoxy.
 20. The method according to claim 1, wherein R⁶is hydrogen.
 21. The method according to claim 19, wherein R⁶ ishydrogen.
 22. The method according to claim 1, wherein R¹ is phenylsubstituted with methyl and/or fluorine, R² is lower-alkyl, R³ ishydrogen, R⁴ is lower-alkyl, R⁵ is lower-alkoxy, and R⁶ is hydrogen. 23.The method according to claim 1, wherein R¹ is 2-methyl-phenyl or2-fluoro-phenyl, R² is methyl, R³ is hydrogen, R⁴ is methyl, R⁵ isethoxy, and R⁶ is hydrogen.
 24. The method according to claim 1, whereinthe compound is selected from the group consisting of:(S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid,(S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionicacid,(S)-2-Ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionicacid,(S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionicacid, and(S)-3-{4-[2-(4-tert-Butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionicacid, or pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.
 25. The method according to claim 1, whereinthe compound is selected from the group consisting of:(S)-2-Ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid, and(S)-2-Ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid, or pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.
 26. The method according to claim 1, whereinthe compound is selected from the group consisting of:(S)-2-Ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid,(S)-2-Ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionicacid,(S)-3-[2-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid,(S)-2-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionicacid,(S)-3-[2,6-Dimethyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionicacid,(S)-3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionicacid, and(S)-2-Ethoxy-3-{2-methyl-4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-phenyl}-propionicacid, or pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.
 27. The method according to claim 1, whereinthe compound is selected from the group consisting of:(S)-2-Ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid,(S)-2-Ethoxy-3-{2-ethyl-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionicacid, and(S)-3-{2-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid, or pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.
 28. The method according to claim 1, whereinthe compound is selected from the group consisting of:(S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid,(S)-3-{2-Chloro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionicacid, and(S)-2-Ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2methyl-phenyl)-propionicacid, or pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.
 29. The method according to claim 1, whereinthe compound is(S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid or pharmaceutically acceptable salts and/or pharmaceuticallyacceptable esters thereof.
 30. The method according to claim 1, whereinthe compound is(S)-2-Ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionicacid.